Gibbledygook's anti-viral log

Tell us what you are using to treat your MS-- and how you are doing.

Postby gibbledygook » Fri Feb 06, 2009 9:07 am

Back to mast cells:

1: Surgery. 1996 May;119(5):494-7.Links
Increased mast cell infiltration in varicose veins of the lower limbs: a possible role in the development of varices.Yamada T, Tomita S, Mori M, Sasatomi E, Suenaga E, Itoh T.
Department of Emergency Medicine, Saga Medical School, Japan.

BACKGROUND. This study shows increased infiltration of mast cells in the walls of varicose veins in the lower limbs as an explanation of the pathogenesis of varix formation. METHODS. Great saphenous veins exhibiting varicosity were histologically examined after vein stripping surgery, and the numbers of mast cells in the varicose lesions were estimated in 20 high-power fields (x400). Normal-looking regions of the veins were referred to as controls, and normal saphenous veins were prepared during coronary artery bypass grafting and designated baseline controls. RESULTS. The varicose lesions showed a greater extent of mast cell infiltration (15.0 +/- 8.4 cells; mean +/- standard deviation), whereas control veins (5.9 +/- 4.0) and baseline control veins (4.4 +/-2.9) had a smaller number of mast cells. CONCLUSIONS. The study suggests that increased mast cell infiltration contributes to the development of varicose veins.

PMID: 8619202 [PubMed - indexed for MEDLINE]
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1: Int Angiol. 2003 Mar;22(1):43-9.Links
Increased mast cell infiltration in familial varicose veins: pathogenetic implications?Kakkos SK, Zolota VG, Peristeropoulou P, Apostolopoulou A, Geroukalos G, Tsolakis IA.
University of Patras Medical School, Patras, Greece.

AIM: Increased infiltration of activated mast cells has been recently implicated in the pathophysiology of varicose veins. The aim of the present study was to investigate a possible association between mast cell infiltration of primary varicose veins and clinical features, which could clarify further varicose vein pathophysiology. METHODS: Seventeen patients, operated on for primary varicose veins and greater saphenous vein incompetence, participated in the study. Mast cells, distributed within the adventitia of grossly abnormal segments of the greater saphenous vein and calf varicosities removed during surgery, were identified and measured in stained tissue sections. The mast cell count, expressed as mast cells per 10 high-power fields, was subsequently associated with clinical features, including age, gender, body mass index, familial varicose veins, duration of varicose vein disease and relation to previous pregnancies, leg symptoms and findings on physical examination, clinical class and score of chronic venous insufficiency (CEAP classification). RESULTS: Patients with family history of varicose veins (n=7) had a significantly increased mast cell infiltration (median, interquartile range) of the abnormal venous segments (16, 8.4) in comparison with those (n=10) without such a history (9.2, 7.3), p=0.005. Mast cell infiltration had a significant inverse association with age (r= -0.49, p=0.046), but not with the remaining clinical features. CONCLUSION: Our findings support the hypothesis that the increased mast cell infiltration in varicose veins is not a consequence of venous hypertension. Furthermore, the increased mast cell infiltration in familial varicose veins implies a rather primary role and therefore the presence of a distinct pathophysiology. Further investigation testing the activity of mast cells in cases of family history might reveal another step in the pathogenic mechanism of varicose veins, leading to a more rational treatment.

PMID: 12771855 [PubMed - indexed for MEDLINE]
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and back to Bax (upregulated by broccoli sprouts)

1: Eur J Vasc Endovasc Surg. 2008 Feb;35(2):224-9. Epub 2007 Oct 23. Links
Association of primary varicose veins with dysregulated vein wall apoptosis.Ducasse E, Giannakakis K, Speziale F, Midy D, Sbarigia E, Baste JC, Faraggiana T.
Unit of Vascular Surgery, Hospital Tripode-Pellegrin, Université de Bordeaux 2, CHU de Bordeaux, Bordeaux, France. eric.ducasse@online.fr

BACKGROUND: Disordered programmed cell death may play a role in the development of superficial venous incompetence. We have determined the number of cells in apoptosis, and the mediators regulating the intrinsic and extrinsic pathways in specimens of varicose vein. METHODS: Venous segments were obtained from 46 patients undergoing surgical treatment for primary varicose veins. Controls samples were obtained from 20 patients undergoing distal arterial bypass grafting surgery. Segments of the distal and proximal saphenous trunk as well as tributaries were studied. Cell apoptoses and mediators of the mitochondrial and trans membrane pathway were evaluated with peroxidase in situ apoptosis detection, Bax and Fas detection, caspase-9 and 8 detection in the medial layer. RESULTS: Disorganised histological architecture was observed in varicose veins. Primary varicose veins also contained fewer peroxidase in situ-positive cells than control veins (2.6% S.D. 0.2% versus 12% S.D. 0.93%, P=.0001, Mann-Whitney u test), fewer Bax positive cells (2.1.% S.D. 0.3% versus 13% S.D. 0.9%, P=.0001) and fewer Caspase 9 positive cells (3.2% S.D. 1% versus 12% S.D. 1.3%, P=.0001). Similar findings were observed in saphenous trunk, main tributaries and accessory veins. In patients with recurrent varicose veins in whom the saphenous trunk had been preserved showed similar findings to primary varicose veins. Residual varicose veins contained fewer peroxidase in situ-positive cells than healthy veins (3.2% S.D. 0.6% versus 11% S.D. 2%, P=.0001), fewer Bax positive cells (2.2% S.D. 0.3% versus 12% S.D. 0.7%, P=.0001) and fewer Caspase 9 positive cells (2.6% S.D. 0.6% versus 12% S.D. 1%, P=.0001). Immunohistochemical detection for Fas and caspase 8 remained equal was the same in the varicose vein and control groups. CONCLUSION: Apoptosis is down regulated in the medial layer of varicose veins. This dysregulation is attributable to a disorder of the intrinsic pathway and involves the great saphenous vein trunk, major tributaries and accessory veins. This process may be among the causes of primary varicose veins.

PMID: 17936650 [PubMed - indexed for MEDLINE]
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but

1: Histol Histopathol. 2000 Jul;15(3):745-52.Links
Evaluation of the smooth muscle cell component and apoptosis in the varicose vein wall.Buján J, Jiménez-Cossio JA, Jurado F, Gimeno MJ, Pascual G, García-Honduvilla N, Dominguez B, Bellón JM.
Department of Morphological Sciences and Surgery, Faculty of Medicine, University of Alcalá, Madrid, Spain. mjulia.bujan@uah.es

This study was designed to evaluate the role of the smooth muscle cell and the apoptosis in the pathogenesis of the varicose vein. Segments of saphenous vein were obtained from healthy subjects and from those with varicose veins. The vein specimens were subdivided according to subject age (younger or older than 50 years) and according to the varicose vein source (distal or proximal). Morphological, ultrastructural, cell proliferation (anti-PCNA method) and cell death (TUNEL method) analysis were performed. The walls of healthy, control vein specimens acquired a more collagenous and papillomatous appearance with age. A slight increase in the number of TUNEL-positive cells was also observed in specimens from older subjects. The proportion of apoptotic cells was much greater in the varicose veins than in control specimens. Most cellular alterations were seen in proximal varicose segments obtained from young subjects. These specimens showed hypertrophic areas with a high degree of cellularity (both in the media and in the thickened intima). The highest proportion of apoptotic cells and collagenisation were also observed in these areas. The enhanced number of apoptotic cells in varicose veins observed mainly in proximal/young vein specimens could be responsible, at least in part, for the acceleration of the final fibrosclerotic process characteristic of the varicose vein wall.

PMID: 10963119 [PubMed - indexed for MEDLINE]
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but then again I think broccoli sprouts must be good since broccoli sprouts upregulate Bax (see Natural section in forum)

1: J Vasc Surg. 2001 May;33(5):1080-6. Links
Expression of molecular mediators of apoptosis and their role in the pathogenesis of lower-extremity varicose veins.Ascher E, Jacob T, Hingorani A, Tsemekhin B, Gunduz Y.
Division of Vascular Surgery, Maimonides Medical Center, Brooklyn, NY, USA.

PURPOSE: In an earlier study, we observed a significant decrease in apoptosis in varicose veins, as compared with healthy veins, indicating that deregulated apoptosis plays a role in the pathogenesis of varicosities. In addition, significant differences were noted in the expression and subcellular localization of the cell cycle regulatory protein, cyclin D1 in varix tissues, as compared with controls. Because cell cycle checkpoint controls are linked to the signaling and execution of apoptotic cascades, we examined the expression of bcl-2 family members bax and bcl-x, known molecular mediators of apoptosis, and that of poly (ADP-ribose) polymerase (PARP), a downstream substrate of DNA cleavage. METHODS: Twenty varicose vein specimens were retrieved from 20 patients (10 men, 10 women; mean age, 53.6 +/- 4.7 years) undergoing lower-extremity varicose vein excision. Healthy greater saphenous vein segments (n = 27) were obtained from 27 patients (14 men, 13 women; mean age, 59.5 +/- 2.4 years) undergoing infrainguinal arterial bypass grafting surgery. All tissues were distal portions. As per CEAP classification for chronic lower-extremity venous disease, most of the patients were in class 2 for clinical signs (n = 11); some patients were in class 3 (n = 4) or class 4 (n = 4), and only one patient was in class 5. Five 5-microm thick sections from formalin-fixed, paraffin-embedded specimens were used as a means of immunohistochemically localizing the expression of bax, bcl-x, and PARP, and 10 random high-power fields per section were evaluated by two independent reviewers blinded to the clinical findings. Statistical analyses were conducted by means of chi(2), analysis of variance, Student and Fisher exact t tests with StatView software. RESULTS: Immunoreactivity to pro-apoptotic bax was significantly higher in the normal veins (P <.001). Cytoplasmic expression of bcl-x was prominent in the cells of the vasa vasorum in both varicose and healthy veins. PARP expression was diminished in the varicose vein group, with 2.8 +/- 0.7 (P =.01) and 1.4 +/- 0.5 (P =.05) cells per high-power field in the intima and media, respectively. Neither bax nor PARP was noted in the adventitia of varicose veins, although their expression was detected in this layer of the control group (P <.001). CONCLUSION: The entry of smooth muscle cells into the apoptotic pathway may be regulated by the induction of bax in this model, because there is significant presence of this pro-apoptotic protein in healthy veins. Both bax and PARP are downregulated in varicose veins, as compared with healthy veins, and this may play a significant role in the pathogenesis of varicose veins.

PMID: 11331852 [PubMed - indexed for MEDLINE]
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maybe calcium dobesilate for apoptosis regulation:

1: Vasa. 2008 Aug;37(3):233-40.Links
Effects of calcium dobesilate and diosmin-hesperidin on apoptosis of venous wall in primary varicose veins.Iriz E, Vural C, Ereren E, Poyraz A, Erer D, Oktar L, Gokgoz L, Halit V, Soncul H.
Gazi University, School of Medicine, Department of Cardiovascular Surgery, Ankara, Turkey. erkaniriz@gmail.com

BACKGROUND: Evaluation of the therapeutic effects of calcium dobesilate and diosmin-hesperidin through regulation of apoptosis. PATIENTS AND METHODS: 56 Patients were divided into four groups; Group 1 consisted of patients (n = 18) with the recent diagnosis of primary varicose disorder who have never used medications, Group 2 consisted of patients (n = 14) who have used diosmin-hesperidin for at least six weeks prior to the operation, Group 3 consisted of patients (n = 14) who have used calcium dobesilate for at least six weeks prior to the operation and finally Group 4 (Control group) consisted of normal saphenous vein biopsies (n = 10). All biopsies were stained with Hematoxylin and Eosin. Tissue samples from 56 patients were immunohistochemically stained with antibodies of anti-bcl-2, anti-bax and anti-p53. Apoptosis was evaluated by TUNEL method. RESULTS: There were no statistically significant differences among the groups in respect to gender distribution and smoking status. Immunohistochemical evaluation of apoptosis related proteins revealed a statistically significant difference between Group 4 and the other groups with respect to the apoptag staining on venous wall (p = 0.026). There were significant differences in the presence of bcl-2 protein expression between groups 4 and Group 1 (p = 0.0002) and between Group 1 and Group 3 (p = 0.023). CONCLUSIONS: Our study highlights the significance of apoptosis in varicose disorders and suggests that calcium dobesilate, which is used in the treatment of varicose veins, could be of benefit by regulating apoptosis.

PMID: 18690590 [PubMed - indexed for MEDLINE]
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transforming growth factor beta 1 seems dysregulated in varicose veins:

1: J Vasc Res. 2007;44(3):192-201. Epub 2007 Feb 27. Links
TGF-beta1 upregulation in the aging varicose vein.Pascual G, Mendieta C, García-Honduvilla N, Corrales C, Bellón JM, Buján J.
Department of Medical Specialities, Faculty of Medicine, University of Alcala, Alcalá de Henares, Madrid, Spain.

BACKGROUND: Although the etiology of venous insufficiency is not well understood, immune response and aging are beginning to emerge as contributing factors. Factors involved in tissue remodeling such as TGF-beta(1) also seem to play an important role in extracellular matrix production. The aim of this study was to explore the relationship between chronic venous insufficiency and TGF-beta(1) examining the latent/mature form of TGF-beta(1) and the presence of mast cells. Effects of age were also evaluated. METHODS: Saphenous veins were obtained from patients subjected to aortocoronary bypass (controls) and undergoing varicose vein surgery. These were immunolabeled using anti-LAP TGF-beta(1)/anti-TGF-beta(1) antibodies and subjected to Western blot. Mast cell population was identified by metachromatic staining. RESULTS: Latent TGF-beta(1) was significantly reduced in varicose veins from older subjects. In contrast, smooth muscle cells obtained from the varicosities showed intense levels. Mature TGF-beta(1) significantly differed between healthy and varicose veins. No mature TGF-beta(1) was detected in the cell cultures. Mast cell number and degranulation were increased with aging and varicose disease, colocalizing with the mature form of TGF-beta(1). CONCLUSION: Aging and varicose pathology induce dysregulation of TGF-beta(1) that could play an important role in the fibrous process, representing the final stages of venous insufficiency.

PMID: 17337905 [PubMed - indexed for MEDLINE]
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seems as though TGF-beta1 is in the areas of stenoses:

1: J Vasc Surg. 2005 Mar;41(3):523-30. Links
Overexpression of transforming growth factor-beta1 correlates with increased synthesis of nitric oxide synthase in varicose veins.Jacob T, Hingorani A, Ascher E.
Division of Vascular Surgery, Maimonides Medical Center, 4802 10th Avenue, Brooklyn, NY 11219, USA.

INTRODUCTION: Transforming growth factor-beta 1 (TGF-beta 1 ) is known to maintain a balance between apoptosis and cellular dysfunction and therefore may have a pivotal role in vessel remodeling during pathogenesis of vascular disorders. We previously demonstrated that inducible nitric oxide synthase (iNOS) mediates signal transduction in vascular wall during the development of varicose veins. Currently, we investigated the expression and correlation of TGF-beta 1 , iNOS, monocyte/macrophage infiltration, and loss of vascular smooth muscle cells (VSMCs), in a series of normal and varicose vein specimens. METHODS: Twenty varicose vein specimens were retrieved from 20 patients undergoing lower-extremity varicose vein excision, and 27 normal greater saphenous vein segments (controls) were obtained from 27 patients undergoing infrainguinal arterial bypass surgery. Principal risk factors (diabetes mellitus, hypertension, tobacco abuse) were also compared. Varicose vein segments were separated into tortuous and nontortuous regions based on their macroscopic and microscopic morphology. VSMC actin, CD68 + monocytes/macrophages, iNOS, and TGF-beta 1 , were examined by immunohistochemistry, immunoblotting, and real-time reverse transcriptase polymerase chain reaction. RESULTS: According to the CEAP classification for chronic lower extremity venous disease, most of the patients were in class 2 for clinical signs of the disease (n = 11). Mean ages were 53.6 +/- 4.7 years for the varicose vein group and 56.5 +/- 4.4 years for the controls. The gender distribution was same in both groups. Immunoreactivity to TGF-beta 1 and iNOS was significantly different in the tortuous regions of the varicose veins compared with nontortuous regions (P < .01). Not only was a significantly higher expression of iNOS noted in the varicose vein group (P < .001), but a differential expression of iNOS was also observed in the tortuous and nontortuous portions of the varicose veins. Significant overexpression of TGF-beta 1 (P < .01) that correlated with overproduction of iNOS and with increased presence of CD68 + monocytes/macrophages was observed in the varicose vein walls compared with normal veins. CONCLUSIONS: This is the first evidence of TGF-beta 1 , as well as iNOS, being differentially upregulated in nontortuous and tortuous segments of varicose veins. The increased expression of TGF-beta 1 and presence of macrophages, correlating with overproduction of iNOS, may be associated with varicosity development and deserves further study. CLINICAL RELEVANCE: The pathogenesis of varicose veins, the most common manifestation of chronic venous disease, is debatable. Elucidation of mechanisms involved in the disease process is the first step to improved therapeutic modulations. Towards this goal, the relationship between NO production and TGF-beta 1 in the molecular pathophysiology of chronic venous disease was investigated. The data identify for the first time, an important role for TGF-b1-iNOS-monocyte/macrophage signaling in the etiology of varicosities. Furthermore, we determine if there are any significant differences within the varicose vein group itself based on regional differences, by classifying the varicose tissues into tortuous and non-tortuous segments.

PMID: 15838489 [PubMed - indexed for MEDLINE]
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seems like TGF-beta1 is a gene commonly expressed in MS. Not sure if the TGF-beta1 above is the same as the gene though...but seems possible...
1: BMC Med Genet. 2008 Mar 19;9:17. Links
Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission.Arthur AT, Armati PJ, Bye C; Southern MS Genetics Consortium, Heard RN, Stewart GJ, Pollard JD, Booth DR.
Department of Medicine and the Nerve Research Foundation, the University of Sydney, Sydney, Australia. ariela@med.usyd.edu.au

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes. METHODS: In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous transcriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level. RESULTS: Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFbeta1, CD58 and DBC1. TGFbeta1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putative promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found. CONCLUSION: The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.

PMID: 18366677 [PubMed - indexed for MEDLINE]
PMCID: PMC2324081
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downregulation of endothelin receptors in varicose tissue:

1: Zhonghua Wai Ke Za Zhi. 2008 Sep 1;46(17):1325-8.Links
[The relationship between endothelin receptors and chronic venous insufficiency of lower extremities][Article in Chinese]


Yang L, Qi GY, Cao YX, Liu J, Zhao M.
Department of General Surgery, the First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710061, China. yl581@sohu.com

OBJECTIVE: To investigate the effect of endothelin receptors in chronic venous insufficiency (CVI) in lower extremities. METHODS: Ten cases of varicose veins from CVI patients (as case group) and ten cases of non-varicose veins (as control group) were investigated in this study. The two groups were divided into two groups respectively: endothelium-intact group and de-endothelium groups. The vasoconstriction mediated by endothelin A (ETA) and endothelin B (ETB) receptors was recorded with myography. The distribution of ETA and ETB receptors was detected by immunohistochemistry method. RESULTS: Endothelin-1 (ET-1) and sarafotoxin 6c (S6c) induced concentration-dependent contraction in the veins. In endothelium-intact veins, the E(max) and pD(2) of contraction curve induced by ET-1 were 132.30% +/- 43.42% and 6.03 +/- 0.35, respectively in control group;and were 19.24% +/- 12.94% and 6.78 +/- 0.46, respectively in case group. The E(max) and pD(2) in case group were much lower than in control group (P < 0.05). The E(max) and pD(2) induced by S6c were 30.10% +/- 12.90% and 6.54 +/- 0.36, respectively in control group, and were 9.61% +/- 1.32% and 6.75 +/- 0.29, respectively in case group; The E(max) in case group was lower than in control group (P < 0.05). In de-endothelium veins, E(max) and pD(2) of S6c were 146.18% +/- 32.33% and 6.50 +/- 0.17 in control group, and 32.93% +/- 3.00% and 6.69 +/- 0.39 in case group; The E(max) in case group was significantly lower than in control group (P < 0.05). ETA receptors was located in endothelium mainly, and ETB receptors in smooth muscle cells mainly. The sites of both ETA and ETB receptors were decreased in case group obviously. CONCLUSIONS: The contraction mediated by ETA receptor and ETB receptor was decreased with a decrease of ETA receptor and ETB receptor sites in varicose veins of CVI. The contraction insufficiency and down-expression of ETA receptor and ETB receptor are correlated with CVI.

PMID: 19094564 [PubMed - in process]
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endothelin effects:

1: Agents Actions Suppl. 1995;45:237-53.Links
Endothelin and endothelin antagonists: pharmacology and clinical implications.Lüscher TF, Wenzel RR.
University Hospital, Inselspital, Bern/Switzerland.

Endothelins (ET) are a family of peptides with potent biological properties. Endothelial cells produce exclusively ET-1 while other tissues produce ET-2 and ET-3. The production of ET requires an increase in intracellular Ca2+. This increase can be induced by physical chemicals (i.e. hypoxia) or receptor-operated stimuli (i.e. thrombin, angiotensin II, arginine vasopressin, transforming growth factor beta 1, interleukin-1). Most of ET is released abluminally towards vascular smooth muscle and less luminally. The main vascular effect of ET are vasodilation (transient), profound and sustained vasoconstriction as well as proliferation of vascular smooth muscle. These biological effects are mediated by distinct receptors. Three ET receptors have been cloned, i.e. ETA-, ETB- and ETC-receptors. In vascular tissue ETA-receptors are expressed on vascular smooth muscle and responsible for vasoconstriction. ETB-receptors are expressed on endothelium and linked to nitric oxide and/or prostacyclin release. Activation of these receptors explains the transient vasodilation with intraluminal application of ET. Vascular smooth muscle cells can express ETB-receptors which contribute to ET-induced vasoconstriction particularly at lower concentrations. The role of the recently cloned ETC-receptor in the vasculature is still uncertain. ET production is increased (as judged from circulating plasma levels) in vascular disease and atherosclerosis in particular, in myocardial infarction and heart failure, pulmonary hypertension and renal disease. ET production is increased in arterial hypertension remains controversial. Non-peptidic ET antagonists have been developed which either block ETA- receptors or ETA- and ETB-receptors simultaneously. The advantage of ETA-receptors is that they leave the endothelium-dependent vasodilation to ET (via ETB-receptor) intact. However, ETB-mediated contraction remains unaffected by these antagonists. In contrast ETA-/ETB-antagonists fully prevent ET-induced vasoconstriction, however, they also inhibit the endothelial effects of the peptide. ET antagonists interfere with the effects of ET in isolated vascular tissue (including that obtained from humans) as well as in vivo. In humans, ETA as well as ETA-/ETB-antagonists inhibit endothelin-induced vasoconstriction. Hence in summary ET are a family of potent peptides with profound effects in the vasculature. Several studies suggest a role of ET in cardiovascular disease. The newly developed ET-antagonists are potent and selective tools to delineate the (patho-)physiological roles of ET and may become a new class of cardiovascular drugs.

PMID: 7717186 [PubMed - indexed for
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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,
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gibbledygook
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Postby gibbledygook » Wed Feb 11, 2009 8:42 am

I have posted above research on Transforming Growth Factor Beta 1 which seems highly expressed around the stenoses in venous insufficiency. Here I've found some herbs which seem to reduce this factor. Here it is described as strongly fibrogenic which might contribute to the build-up of tissue in venous stenoses:

1: J Cell Biochem. 2008 Jun 1;104(3):908-19. Links
Safflower extract: a novel renal fibrosis antagonist that functions by suppressing autocrine TGF-beta.Yang YL, Chang SY, Teng HC, Liu YS, Lee TC, Chuang LY, Guh JY, Chang FR, Liao TN, Huang JS, Yeh JH, Chang WT, Hung MY, Wang CJ, Chiang TA, Hung CY, Hung TJ.
Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan. call0955443221@gmail.com

Progressive renal disease is characterized by the accumulation of extracellular matrix proteins in the renal interstitium. Hence, developing agents that antagonize fibrogenic signals is a critical issue facing researchers. The present study investigated the blood-circulation-promoting Chinese herb, safflower, on fibrosis status in NRK-49F cells, a normal rat kidney interstitial fibroblast, to evaluate the underlying signal transduction mechanism of transforming growth factor-beta (TGF-beta), a potent fibrogenic growth factor. Safflower was characterized and extracted using water. Renal fibrosis model was established both in vitro with fibroblast cells treated with beta-hydroxybutyrate and in vivo using rats undergone unilateral ureteral obstruction (UUO). Western blotting was used to examine protein expression in TGF-beta-related signal proteins such as type I and type II TGF-beta receptor, Smads2/3, pSmad2/3, Smads4, and Smads7. ELISA was used to analyze bioactive TGF-beta1 and fibronectin levels in the culture media. Safflower extract (SE) significantly inhibited beta-HB-induced fibrosis in NRK cells concomitantly with dose-dependent inhibition of the type I TGF-beta1 receptor and its down-stream signals (i.e., Smad). Moreover, SE dose-dependently enhanced inhibitory Smad7. Thus, SE can suppress renal cellular fibrosis by inhibiting the TGF-beta autocrine loop. Moreover, remarkably lower levels of tissue collagen were noted in the nephron and serum TGF-beta1 of UUO rats receiving oral SE (0.15 g/3 ml/0.25 kg/day) compared with the untreated controls. Hence, SE is a potential inhibitor of renal fibrosis. We suggest that safflower is a novel renal fibrosis antagonist that functions by down-regulating TGF-beta signals.

PMID: 18189272 [PubMed - indexed for
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1: Zhonghua Gan Zang Bing Za Zhi. 2008 Mar;16(3):193-7.Links
[Inhibiting effects of denshensu, baicalin, astragalus and Panax notoginseng saponins on hepatic fibrosis and their possible mechanisms][Article in Chinese]


Li X, Peng XD, Zhang WL, Dai LL.
Department of Gastroenterology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.

OBJECTIVE: To study the anti-fibrotic effects of danshensu, baicalin, astragalus and Panax notoginseng saponins (PNS) and their possible mechanisms. METHODS: The four Chinese herb products mentioned above were given intraperitoneally to experimental rats with hepatic fibrosis. Colchicine was administered to a control group. Comparisons were made in four aspects: (1) Degrees of liver fibrosis; (2) Serum levels of hyaluronic acid (HA) and type IV collagen (CIV), using radioimmunoassay; (3) Densities of malondialdehyde (MDA), superoxide dismutase (SOD) and hydroxyproline (Hyp), using chromatometry, to detect the expression of tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), matrix metalloproteinase-1(MMP-1) and transforming growth factor beta 1 (TGF beta 1) in liver tissues, using immunhistochemical techniques; and (4) For hepatic stellate cells (HSCs): proliferation using MMT calorimetric assay, the cell cycles using flow cytometry, apoptosis using AO/EB fluorescence staining and type I and type III collagens using immunocytochemical stainings. RESULTS: (1) Compared with the model group, the serum levels of HA and CIV decreased significantly in all four drug-treated groups, especially in the danshensu-treated group. Astragalus and baicalin had better effects over PNS (P<0.05 or 0.01). (2) In contrast to the model group, all four drugs dramatically reduced the amount of Hyp and MDA, increased SOD activity and reduced the degrees of liver fibrosis and the expressions of TIMP-1 and TGFbeta1 in liver tissues (P<0.05 or 0.01). Danshensu had the best effect, astragalus and baicalin had similar effects which were stronger than PNS. (3) All four drugs inhibited HSCs proliferation, induced HSCs apoptosis and decreased type I, III collagen synthesis of HSC. CONCLUSIONS: The four drugs could minimize the hepatic fibrosis of rats in different degrees. Danshensu had the best effect, astragalus and baicalin had similar effects. The possible mechanisms of these effects might be related to inhibiting actions on activation and proliferation, promoting apoptosis and lowering the expression of type I and type III collagen of HSCs by down-regulating the expression of TGFbeta1; the decrease in the amount of MDA and the increase of SOD activity; and the reduction of extracellular matrix by down-regulation of TIMP-1/MMP-1.

PMID: 18364078 [PubMed - in process]
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Interestingly, all the above herbs are in my latest tea which I have found has a very noticeable effect on my leg and is so strong I'm only taking one spoon of it.


1: Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007 Aug;27(8):728-31.Links
[Effect of astragaloside on myocardial fibrosis in chronic myocarditis][Article in Chinese]


Zhang ZC, Li SJ, Yang YZ.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai.

OBJECTIVE: To investigate the effect of astragaloside (Astr), one of the active components of the Chinese medical herb Astragulus membranaceus, on cardiac fibrosis in chronic myocarditis and its relevant mechanisms. METHODS: Eighty mice were randomized into 3 groups, the control group (n=20), the model group (n=30) and the Astr group (n=30). Mice in the model group and the Astr group were monthly intraperitoneally inoculated with CVB3, but to the control group equal amount of culture fluid was given instead. Mice in the control and the model group were fed with drinking water while those in the Astr group with drinking water containing Astr-sodium carboxymethycellulose at a concentration of 300 mg/L. All the survived mice were sacrificed 3 months later. Heart tissue of mice was stained by picrosirius red for calculating collagen volume fraction (CVF) with an automatic image analysis system. Expressions of transforming growth factor beta1 (TGF-beta1), platelet derived growth factor (PDGF), matrix metalloproteinase 1 (MMP-1), tissue inhibitor of metalloproteinase 1 (TIMP-1), MMP-13 and MMP-14 in heart tissue were detected by Western blot analysis. RESULTS: As compared with the model group, in the Astr group, the mortality and CVF were significantly lower (53.3% vs. 23.3%, chi2 = 4.23, P < 0.05), and (17.4 +/- 1.2% vs. 8.6 +/- 0.9%, chi2 = 5.38, P < 0.05), respectively. As compared with the control group, Western blot analysis showed that expression of TGF-beta1 was decreased, MMP-1 and TIMP-1 were down-regulated, while expressions of MMP-13 and MMP-14 were up-regulated after Astr treatment. CONCLUSION: Astr could lower the mortality and alleviate the myocardial fibrosis of mice with chronic myocarditis. Its antifibrotic effect might be realized by way of inhibiting TGF-beta1 expression and up-regulating the expressions of MMP-13 and MMP-14 in the heart tissues.

PMID: 17879539 [PubMed - indexed for MEDLINE]
link
I took astragalus in large quantities during the summer of 2008 and this seemed to provoke rather a lot of spasms so I backed off but I might add this on the days when I can't stomach the tea.



Another reason to downregulate TGF beta 1:
1: J Clin Invest. 2007 Nov;117(11):3306-15. Links
Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis.Luo J, Ho PP, Buckwalter MS, Hsu T, Lee LY, Zhang H, Kim DK, Kim SJ, Gambhir SS, Steinman L, Wyss-Coray T.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305-5235, USA.

Autoimmune encephalomyelitis, a mouse model for multiple sclerosis, is characterized by the activation of immune cells, demyelination of axons in the CNS, and paralysis. We found that TGF-beta1 synthesis in glial cells and TGF-beta-induced signaling in the CNS were activated several days before the onset of paralysis in mice with autoimmune encephalomyelitis. While early production of TGF-beta1 was observed in glial cells TGF-beta signaling was activated in neurons and later in infiltrating T cells in inflammatory lesions. Systemic treatment with a pharmacological inhibitor of TGF-beta signaling ameliorated the paralytic disease and reduced the accumulation of pathogenic T cells and expression of IL-6 in the CNS. Priming of peripheral T cells was not altered, nor was the generation of TH17 cells, indicating that this effect was directed within the brain, yet affected the immune system. These results suggest that early production of TGF-beta1 in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation, providing a rare example of the brain modulating the immune system. Importantly, inhibition of TGF-beta signaling may have benefits in the treatment of the acute phase of autoimmune CNS inflammation.

PMID: 17965773 [PubMed - indexed for MEDLINE]
link

ON the other hand:
1: J Immunol. 2007 Apr 1;178(7):4632-40. Links
TGF-beta1-mediated control of central nervous system inflammation and autoimmunity through the inhibitory receptor CD26.Preller V, Gerber A, Wrenger S, Togni M, Marguet D, Tadje J, Lendeckel U, Röcken C, Faust J, Neubert K, Schraven B, Martin R, Ansorge S, Brocke S, Reinhold D.
Institute of Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.

The T cell marker CD26/dipeptidyl peptidase (DP) IV is associated with an effector phenotype and markedly elevated in the human CNS disorder multiple sclerosis. However, little is known about the in vivo role of CD26/DP IV in health and disease, and the underlying mechanism of its function in CNS inflammation. To directly address the role of CD26/DP IV in vivo, we examined Th1 immune responses and susceptibility to experimental autoimmune encephalomyelitis in CD26(-/-) mice. We show that gene deletion of CD26 in mice leads to deregulation of Th1 immune responses. Although production of IFN-gamma and TNF-alpha by pathogenic T cells in response to myelin Ag was enhanced in CD26(-/-) mice, production of the immunosuppressive cytokine TGF-beta1 was diminished in vivo and in vitro. In contrast to the reduction in TGF-beta1 production, responsiveness to external TGF-beta1 was normal in T cells from CD26(-/-) mice, excluding alterations in TGF-beta1 sensitivity as a mechanism causing the loss of immune regulation. Natural ligands of CD26/DP IV induced TGF-beta1 production in T cells from wild-type mice. However, natural ligands of CD26/DP IV failed to elicit TGF-beta1 production in T cells from CD26(-/-) mice. The striking functional deregulation of Th1 immunity was also seen in vivo. Thus, clinical experimental autoimmune encephalomyelitis scores were significantly increased in CD26(-/-) mice immunized with peptide from myelin oligodendrocyte glycoprotein. These results identify CD26/DP IV as a nonredundant inhibitory receptor controlling T cell activation and Th1-mediated autoimmunity, and may have important therapeutic implications for the treatment of autoimmune CNS disease.

PMID: 17372022 [PubMed - indexed for MEDLINE]
link

AND

1: Biochem Biophys Res Commun. 2007 Apr 13;355(3):776-81. Epub 2007 Feb 14. Links
Semliki Forest virus vectors expressing transforming growth factor beta inhibit experimental autoimmune encephalomyelitis in Balb/c mice.Vähä-Koskela MJ, Kuusinen TI, Holmlund-Hampf JC, Furu PT, Heikkilä JE, Hinkkanen AE.
Department of Biochemistry and Pharmacy, Abo Akademi University, Tykistökatu 6A, FI-20520 Turku, Finland. makoskel@abo.fi

Cytokine immunomodulation of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, has remained a formidable treatment option, but access into the CNS is hampered due to the impermeability of the blood-brain barrier. In this report, we describe the construction and characterization of CNS-homing gene delivery/therapy vectors based on avirulent Semliki Forest virus (SFV) expressing either native or mutant transforming growth factor beta 1 (TGF-beta1). Biological activity of the expressed inserts was demonstrated by PAI-1 promoter driven luciferase production in mink cells and TGF-beta1 mRNA was demonstrated in the CNS of virus treated mice by in situ hybridization and RT-PCR. Both vectors, when given intraperitoneally to EAE mice significantly reduced disease severity compared to untreated mice. Our results imply that immunomodulation by neurotropic viral vectors may offer a promising treatment strategy for autoimmune CNS disorders.

PMID: 17316567 [PubMed - indexed for MEDLINE]
link

1: Neurobiol Dis. 2006 Dec;24(3):484-91. Epub 2006 Sep 26. Links
Extensive extracellular matrix depositions in active multiple sclerosis lesions.van Horssen J, Bö L, Dijkstra CD, de Vries HE.
Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, PO Box 7057, 1007 MB Amsterdam, The Netherlands. j.vanhorssen@vumc.nl

In the central nervous system, basement membrane (BM) constituents are predominantly associated with the vasculature. However, under inflammatory conditions, the expression of BM components may alter. Here, we investigated the distribution of several BM components, including laminin, collagen type IV and heparan sulfate proteoglycans in various multiple sclerosis (MS) lesions. We observed irregular and discontinuous BMs in active lesions. Throughout active MS lesions, we found dense networks of BM proteins, which were surprisingly not associated with the cerebrovasculature. These striking parenchymal networks were not observed in chronic inactive MS lesions and brains of non-neurological controls. In addition, we studied the distribution of transforming growth factor-beta1 (TGF-beta1), since it is known as a major modulator of ECM production. Leukocytes, in particular CD68-positive macrophages, expressed high levels of TGF-beta1 and were located in close proximity to parenchymal BM deposits in the MS lesions. We postulate that these BM networks may play a role in the further recruitment of inflammatory cells and form a barrier for axonal regeneration.

PMID: 17005408 [PubMed - indexed for MEDLINE]
link

so maybe TGF-beta1 is good in some respects but bad for axonal regeneration because it builds up the ECM. mmm.




The fact that mast cells are implicated in varicosities suggests that I must continue to take capsaicin which inhibits masts cells and is very good at reducing my hayfever symptoms. It is also great for my bowel function and I take 600mg at every meal with 2 acidophilus. I've been regular for months now.

I continue to feel much much better since starting the broccoli sprouts in early january and am feeling stronger and stronger in my legs. I even carried half a case of wine up the stairs from the basement yesterday. I wouldn't have dreamt of so doing last year. What is staggeringly noticeable is the bladder function. I am sleeping through the night without needing the toilet 2 to 3 times as was the case for the last 4 years. I also no longer have urgency during the day. I was beginning to wonder whether I was dehydrated but I had a general health check up a few weeks ago and my hydration was fine. I also note that my uric acid levels are higher than normal. This is the first time since diagnosis that my uric acid level has been higher than reference. When I had a mini-relapse at Christmas I took 6grams of inosine a day for about 4 weeks so I'm no taking only 2 grams a day. every little helps.

I have noticed that I cannot take my Chinese tea which has all of the above ingredients except safflower (available at iherb in oil format) nor my salvia/ginkgo on days after ANY alcohol and so instead I take a couple of quercetin tablets. Indeed since starting the broccoli sprouts I'm finding alcohol consumption very unpleasant on the day after, something from which I never suffered previously. Perhaps I'm getting too old (37) but it does seem to be something to do with the broccoli sprouts. So except for post-alcohol days I take 1020mg salvia with 1500mg of source naturals broccoli sprouts and 800mg of life extension broccoli sprouts with curcumin, inosine, scutellaria baicalensis, astaxanthin, vit d,e,c,b, NAC, zinc, calcium, magnesium, pycnogenol. I alternate days of 1020mg salvia with chinese tea. I think I shall add back some astragalus but in low dose.
Any herb/supplement that helps reduce fibrogenesis or smooth muscle cell build-up is interesting.
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,
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Postby gibbledygook » Fri Feb 13, 2009 8:50 am

This suggests that even if we remove the stenoses via stents we'll still have high levels of leukocytes (perhaps because stents don't actually stop the aberrant build-up of smooth muscle cells in the varicose vein). Indeed the researchers suggest the leukocytes may be the primary etiology of CVI.


1: Cardiovasc Surg. 2002 Oct;10(5):464-9. Links
Platelet-monocyte aggregates in patients with chronic venous insufficiency remain elevated following correction of reflux.Rohrer MJ, Claytor RB, Garnette CS, Powell CC, Barnard MR, Furman MI, Michelson AD.
Division of Vascular Surgery and the Center for Platelet Function Studies, The University of Massachusetts Medical School, 55 Lake Avenue, North Worcester 01655, USA. RohrerM@ummhc.org

INTRODUCTION: An increased number of circulating platelet-monocyte aggregates (PMAs) is present in patients with all clinical classes of chronic venous insufficiency (CVI). The purpose of this study was to determine whether patients with CVI maintain elevated levels of PMAs following complete surgical correction of chronic venous insufficiency. METHODS: Patients with superficial venous insufficiency and a normal deep venous system documented by duplex scan were included in the study. Venous blood was drawn from a superficial vein in the leg and an antecubital vein prior to vein stripping and again six weeks postoperatively. Control subjects without evidence of venous disease had blood drawn from an antecubital vein. Whole blood flow cytometry was used to analyze the samples for the presence of platelet-monocyte aggregates following incubation with buffer or 0.5 microM adenosine diphosphate (ADP). RESULTS: Postoperative duplex scanning demonstrated elimination of venous reflux in the superficial venous system and normal deep vein physiology in all nine patients. Preoperatively, patients with CVI had significantly elevated levels of circulating PMAs in both arm and leg samples without stimulation by an agonist compared to controls (15.2+/-1.1 and 14.3+/-1.3 vs 7.4+/-0.3 for controls, p<0.02 for each), and after stimulation by 0.5 microM ADP (33.7+/-4.7 and 34.3+/-5.2 vs 12.5+/-3.8 for controls, p<0.04 for each). There was no significant change in the number of PMAs in either patient arm or leg blood samples six weeks following correction of venous reflux by removal of the diseased veins. CONCLUSIONS: Complete correction of chronic venous insufficiency did not diminish the elevated circulating levels of platelet-monocyte aggregates. We conclude that the presence of an increased number of PMAs identified in patients with CVI is not secondary to the presence of venous reflux, but may be involved with the primary etiology of chronic venous insufficiency. This finding also suggests that a stimulus other than venous hypertension may be important in triggering the leukocyte activation seen in patients with chronic venous disease.

PMID: 12379404 [PubMed - indexed for MEDLINE]
link
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,
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Postby mrhodes40 » Fri Feb 13, 2009 10:00 am

Well it makes sense these things are multi dimensional so platelet aggregates may be somthing one has to deal with, serrapeptase anyone?
:lol:
I like this part:
RESULTS: Postoperative duplex scanning demonstrated elimination of venous reflux in the superficial venous system and normal deep vein physiology in all nine patients.

:D

I an only imagine that IF we do discover with time that people with MS do all show the Zamboni changes, namely reflux, repair, so that the venous system works correctly, can only be helpful.

I get to go the 13th or March. do you have a person to attempt replication of the Zamboni work all lined up?
ANd BTW if you go to the cxsymposium being close as you are you will have to report............... 8)
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Postby gibbledygook » Fri Feb 13, 2009 10:48 am

I'd love to go to the symposium but I'm in South Africa then. I'm going to have to try a different route for the scanning as I haven't heard a thing back from the neurologist who told me I wouldn't be allowed to attend the symposium!!! What a supercilious **** he was. If you pay you go, I reckon.

I also firmly believe that we need to get rid of the stenoses/varicose veins as I think that these are what cause such damage in the CNS. With less pressure on the vein walls the leukocytes just circulate in the blood.

I think the broccoli sprouts are said to reduce leukocytes via apoptosis but I need to check the Natural section again or possibly my own forum!
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,
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Postby gibbledygook » Fri Feb 13, 2009 10:57 am

Yes, there's an abstract in the Natural section on broccoli sprouts which describes how sulforaphane, the active part of broccoli sprouts, kills off T lymphoblastoid Jurkat leukemia cells and upregulates bax which is downregulated in MS and which helps with apoptosis.
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,
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Postby gibbledygook » Mon Feb 16, 2009 8:42 am

here's some stuff on centenella which looks helpful.

1: Angiology. 2001 Oct;52 Suppl 2:S9-13.Links
Total triterpenic fraction of Centella asiatica in chronic venous insufficiency and in high-perfusion microangiopathy.Incandela L, Cesarone MR, Cacchio M, De Sanctis MT, Santavenere C, D'Auro MG, Bucci M, Belcaro G.
Vascular Unit, Ealing Hospital, London, UK.

Total triterpenic fraction of Centella asiatica (TTFCA) is effective in improving venous wall alterations in chronic venous hypertension and in protecting the venous endothelium. TTFCA is active on connective tissue modulation, improves the synthesis of collagen and other tissue proteins by modulating the action of fibroblasts in the vein wall, and stimulates collagen remodeling in and around the venous wall. This is due to the modulating action of TTFCA on fibroblasts as shown by experiments on the growth of human embryonal fibroblasts. TTFCA has a moderate in-vitro and in-vivo stimulating effect on collagen synthesis and, at higher dosages, an inhibition on the synthesis of collagen and acid mucopolysaccharides. Studies have indicated the role of TTFCA on the synthesis of specific venous wall elements by cell cultures of human embryonal fibroblasts. The tissue-stimulating action is shown by the increased collagen production independent from the stimulation of cell proliferation (this differentiates the action of TTFCA from cell growth factors). TTFCA is active on the microcirculation in venous and diabetic microangiopathy. Signs and symptoms of venous hypertension and edema are improved by treatment. The remodeling on collagen synthesis could be one of the possible mechanisms of actions of TTFCA in the remodeling of echolucent (soft; therefore, with risk of thrombosis and embolization) plaques at the carotid and femoral bifurcation. This compound is safe and well tolerated. In conclusion, several actions of TTFCA in vascular diseases makes the use of this compound very interesting in venous and arterial problems.

PMID: 11666128 [PubMed - indexed for MEDLINE]
linl
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,
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yellow sweet clover

Postby gibbledygook » Tue Feb 17, 2009 3:35 am

yellow sweet clover/melilotus officinalis:

1: Minerva Cardioangiol. 2003 Aug;51(4):411-6.Links
[Chronic venous insufficiency: an open trial of FLEBS Crema][Article in Italian]


Consoli A.
Docente di Fisiopatologia Chirurgica, Università degli Studi di Catania, Catania, Italy.

AIM: This study was realized to evaluate the FLEBS CREMA tolerability and its therapeutic efficacy, in patients with functional disease linked to not complicated venous or lymphatic insufficiency. This compound acts as vasoconstrictor thanks to the vegetable extract of Ruscus aculeatus, but it is also able to reduce the edema, thanks to the vegetable extract of Melilotus officinalis. METHODS: All the patients were treated for three weeks with FLEBS CREMA, that was applied 2 or 3 times a day, on both legs. The traditional clinical parameters of chronic venous insufficiency (IVC) (edema, pain, heaviness, itch, cramps and other symptoms) were evaluated during the treatment. RESULTS: The results show an improvement for all the monitored symptoms, also if the positive clinical response was different for each evaluated parameter. The best results were obtained for edema, pain, heaviness and itch: the statistical analysis shows indeed a significant difference between the beginning and the end of the treatment. In this study the dermo-cosmetic qualities and the tolerability of FLEBS CREMA were also evaluated: both these parameters obtained a positive clinical evaluation. CONCLUSIONS: Basing on these data, the final evaluation for this compound was good/very good for the 80-90% both doctor and patients.

PMID: 12900723 [PubMed - indexed for MEDLINE]
link

LUMBROKINASE - back to fibrinolysis:

1: J Tradit Chin Med. 2003 Jun;23(2):141-6.Links
The effect of lumbrokinase on P-selectin and E-selectin in cerebral ischemia model of rat.Zhang X, Zhang J, Kuang P, Lang S, Wu W, Yuan Y, Liu J, Liu Y, Kuang P.
Department of Neurology, PLA261 Hospital, Beijing, 100094.

PURPOSE: To find the effect of lumbrokinase (LK) on P-selectin and E-selectin in ischemic rats. METHODS: Male healthy Spragur-Dawley rats weighing 180-220 g (n = 90) were divided into 4 groups: (1) normal control group (n = 5), (2) sham-operated group (n = 35), (3) ischemic group (n = 35), (4) LK group (n = 15). LK 10 mg/kg (2000 UK activity of LK) was given by intraperitoneal injection in the LK group 30 minutes before experiment. Same volume of normal saline was given in the sham-operated group and ischemic group. The ischemic model was made by modified Haruo Nagasawa's method. Immunohistochemistry was used to observe the P-selectin and E-selectin positive cells in the ischemic region. RESULTS: P-selectin and E-selectin positive cells in ischemic regions were observed in the ischemic group, and the peak of expression was at 6 hours and 12 hours, respectively. The similar changes were not observed in normal control group. There were only a few positive cells in the sham-operated group. In LK group, the P-selectin and E-selectin positive cells were significantly less than those in the ischemic group (P < 0.05 at 3 hours after the onset, P < 0.01 at 6 hours and P < 0.01 at 12 hours, respectively). CONCLUSIONS: LK might significantly decrease the immunoreactions of P-selectin and E-selectin in ischemic lesion.

PMID: 12875085 [PubMed - indexed for MEDLINE]
link


1: J Neuroinflammation. 2008 Jun 27;5:27. Links
Evidence of platelet activation in multiple sclerosis.Sheremata WA, Jy W, Horstman LL, Ahn YS, Alexander JS, Minagar A.
Multiple Sclerosis Center and Department of Neurology Miller School of Medicine, University of Miami, Miami, Florida, USA. sheremaw@bellsouth.net

OBJECTIVE: A fatality in one multiple sclerosis (MS) patient due to acute idiopathic thrombocytopenic purpura (ITP) and a near fatality in another stimulated our interest in platelet function abnormalities in MS. Previously, we presented evidence of platelet activation in a small cohort of treatment-naive MS patients. METHODS: In this report, 92 normal controls and 33 stable, untreated MS patients were studied. Platelet counts, measures of platelet activation [plasma platelet microparticles (PMP), P-selectin expression (CD62p), circulating platelet microaggragtes (PAg)], as well as platelet-associated IgG/IgM, were carried out. In addition, plasma protein S activity was measured. RESULTS: Compared to controls, PMP were significantly elevated in MS (p < 0.001) and CD62p expression was also markedly elevated (p < 0.001). Both are markers of platelet activation. Platelet-associated IgM, but not IgG, was marginally elevated in MS (p = 0.01). Protein S in MS patients did not differ significantly from normal values. CONCLUSION: Platelets are significantly activated in MS patients. The mechanisms underlying this activation and its significance to MS are unknown. Additional study of platelet activation and function in MS patients is warranted.

PMID: 18588683 [PubMed - indexed for MEDLINE]
PMCID: PMC2474601
link

1: J Neuroimmunol. 2005 Oct;167(1-2):143-9. Links
Plasma levels of soluble adhesion molecules sPECAM-1, sP-selectin and sE-selectin are associated with relapsing-remitting disease course of multiple sclerosis.Kuenz B, Lutterotti A, Khalil M, Ehling R, Gneiss C, Deisenhammer F, Reindl M, Berger T.
Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.

Adhesion molecule mediated leukocyte migration into the central nervous system is considered to be a critical step in the pathogenesis of multiple sclerosis (MS). We measured plasma levels of the soluble adhesion molecules sPECAM-1, sP-selectin and sE-selectin in 166 MS patients and in 36 healthy blood donors with ELISA. sPECAM-1, sP-selectin and sE-selectin plasma concentrations showed a significant increase in the relapsing-remitting disease course of MS and were elevated during relapse. These findings indicate that sPECAM-1, sP-selectin and sE-selectin might be implemented as paraclinical markers of disease activity in MS with restriction to the clinical course of the disease.

PMID: 16040131 [PubMed - indexed for MEDLINE]
link


GALLIC ACID:

1: J Immunol. 2005 May 1;174(9):5805-13. Links
Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII.Piccio L, Rossi B, Colantonio L, Grenningloh R, Gho A, Ottoboni L, Homeister JW, Scarpini E, Martinello M, Laudanna C, D'Ambrosio D, Lowe JB, Constantin G.
Department of Pathology, University of Verona, Verona, Italy.

Lymphocyte migration into the brain represents a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms controlling the recruitment of lymphocytes to the CNS via inflamed brain venules are poorly understood, and therapeutic approaches to inhibit this process are consequently few. In this study, we demonstrate for the first time that human and murine Th1 lymphocytes preferentially adhere to murine inflamed brain venules in an experimental model that mimics early inflammation during EAE. A virtually complete inhibition of rolling and arrest of Th1 cells in inflamed brain venules was observed with a blocking anti-P-selectin glycoprotein ligand 1 Ab and anti-E- and P-selectin Abs. Th1 lymphocytes produced from fucosyltransferase (FucT)-IV(-/-) mice efficiently tethered and rolled, whereas in contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VII(-/-) or Fuc-VII(-/-)FucT-IV(-/-) mice was drastically reduced, indicating that FucT-VII is critical for the recruitment of Th1 cells in inflamed brain microcirculation. Importantly, we show that Abs directed against cutaneous lymphocyte Ag (CLA), a FucT-VII-dependent carbohydrate modification of P-selectin glycoprotein ligand 1, blocked rolling of Th1 cells. By exploiting a system that allowed us to obtain Th1 and Th2 cells with skin- vs gut-homing (CLA(+) vs integrin beta(7)(+)) phenotypes, we observed that induced expression of CLA on Th cells determined a striking increase of rolling efficiency in inflamed brain venules. These observations allow us to conclude that efficient recruitment of activated lymphocytes to the brain in the contexts mimicking EAE is controlled by FucT-VII and its cognate cell surface Ag CLA.

PMID: 15843584 [PubMed - indexed for MEDLINE]
link

1: Arch Biochem Biophys. 2004 May 1;425(1):51-7. Links
Inhibition of fucosyltransferase VII by gallic acid and its derivatives.Niu X, Fan X, Sun J, Ting P, Narula S, Lundell D.
Department of Immunology, Schering Plough Research Institute, 2015 Galloping Hill Road, K-15-3945, Kenilworth, NJ 07033, USA. xiaoda.niu@spcorp.com

Gallic acid (GA) and several gallate derivatives were identified as inhibitors of fucosyltransferase VII (FucT VII). The inhibition by GA and (-)-epigallocatechin gallate (EGCG) is time-dependent and irreversible. GA and EGCG showed inhibition with IC(50) of 60 and 700 nM, respectively, after pre-incubation with FucT VII in the presence of MnCl(2). Absence of MnCl(2) results in significantly weaker inhibition. Complexation of Mn(2+) with GA, EGCG, and gallate esters was observed. Such complexation, however, is not rate-limiting for the inhibition of FucT VII. Therefore, time-dependent inhibition of fucosyltransferases by GA and EGCG is likely due to the slow inactivation by the inhibitors or Mn-inhibitor complex. Although Mg(2+) or Ca(2+) can replace Mn(2+) for FucT VII activation, none forms a complex with GA or EGCG and hence results in weaker inhibition of FucT VII. GA and EGCG also inhibit FucT IV and alpha2,3-(N)-sialyltransferase in the low micromolar range. The structure-function divergence could be observed, as EGCG, but not GA or gallate esters, inhibits Zn(2+) containing metalloproteases such as TNFalpha convertase, matrix metalloproteases 2 and 7.

PMID: 15081893 [PubMed - indexed for MEDLINE]
link

back to TEGF-1 which is strongly expressed in the contorted bits of the varicose vein

1: J Immunol. 2000 Nov 1;165(9):5011-6. Links
Potent induction of alpha(1,3)-fucosyltransferase VII in activated CD4+ T cells by TGF-beta 1 through a p38 mitogen-activated protein kinase-dependent pathway.Wagers AJ, Kansas GS.
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611, USA.

Homing of effector T cells to sites of inflammation, particularly in the skin, is dependent on T cell expression of ligands for the endothelial selectins. Underlying expression of these ligands is the expression of alpha(1,3)-fucosyltransferase VII (FucT-VII), a FucT essential for biosynthesis of selectin ligands. FucT-VII is sharply induced in activated T cells by IL-12, but cytokines other than IL-12 that induce FucT-VII and functional selectin ligands have not been identified, and are likely to be important in homing of T cells to other selectin-dependent sites. Screening of a number of cytokines known to be active on T cells identified only TGF-beta1 as able to up-regulate FucT-VII mRNA levels and selectin ligands on activated CD4 T cells. The sharp increase in FucT-VII induced by TGF-beta1 in activated T cells was completely blocked by pharmacologic inhibition of p38 mitogen-activated protein kinase, but was unaffected by mitogen-activated protein/extracellular signal-related kinase kinase inhibitors. The selective ability of TGF-beta1 to induce selectin ligands on activated T cells is likely important for T cell homing to the gut, which is a strongly selectin-dependent site, and correlates with the ability of TGF-beta1 to coordinately induce other gut-associated homing pathways.

PMID: 11046029 [PubMed - indexed for MEDLINE]
link


nattokinase like lumbrokinase:

1: Clin Hemorheol Microcirc. 2006;35(1-2):139-42. Links
Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity.Pais E, Alexy T, Holsworth RE Jr, Meiselman HJ.
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

The vegetable cheese-like food, natto, is extremely popular in Japan with a history extending back over 1000 years. A fibrinolytic enzyme, termed nattokinase, can be extracted from natto; the enzyme is a subtilisin-like serine protease composed of 275 amino acid residues and has a molecular weight of 27.7 kDa. In vitro and in vivo studies have consistently demonstrated the potent pro-fibrinolytic effect of the enzyme. However, no studies to date have evaluated the effects of nattokinase on various hemorheological parameters and thus we have begun to assess the effects of the enzyme on RBC aggregation and blood viscosity. Blood samples were incubated with nattokinase (final activities of 0, 15.6, 31.3, 62.5 and 125 units/ml) for 30 minutes at 37 degrees C. RBC aggregation was measured using a Myrenne MA-1 aggregometer and blood viscosity assessed over 1-1000 s(-1) with a computer controlled scanning capillary rheometer (Rheolog). Our in vitro results showed a significant, dose-dependent decrease of RBC aggregation and low-shear viscosity, with these beneficial effects evident at concentrations similar to those achieved in previous in vivo animal trials. Our preliminary data thus indicate positive in vitro hemorheological effects of nattokinase, and suggest its potential value as a therapeutic agent and the need for additional studies and clinical trials.

PMID: 16899918 [PubMed - indexed for MEDLINE]
link

nattokinase stops build-up of the intima, part of blood vessel:

1: Life Sci. 2003 Jul 25;73(10):1289-98. Links
Dietary supplementation of fermented soybean, natto, suppresses intimal thickening and modulates the lysis of mural thrombi after endothelial injury in rat femoral artery.Suzuki Y, Kondo K, Matsumoto Y, Zhao BQ, Otsuguro K, Maeda T, Tsukamoto Y, Urano T, Umemura K.
Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu City, Shizuoka 431-3192, Japan. yapplel@hama-med.ac.jp

We have previously demonstrated that natto-extracts containing nattokinase (NK) inactivates plasminogen activator inhibitor type 1 and then potentiates fibrinolytic activity. In the present study, we investigated the effects of dietary supplementation with natto-extracts on neointima formation and on thrombolysis at the site of endothelial injury. Endothelial damage in the rat femoral artery was induced by intravenous injection of rose bengal followed by focal irradiation by transluminal green light. Dietary natto-extracts supplementation containing NK of 50 or 100 CU/body was started 3 weeks before endothelial injury and then continued for another 3 weeks. Intimal thickening in animals given supplementation was significantly (P<0.01) suppressed compared with controls and the intima/media ratio in animals with 50 and 100 CU/body NK and control group was 0.09 +/- 0.03, 0.09 +/- 0.06 and 0.16 +/- 0.12, respectively. Although femoral arteries were reopened both in control animals and those treated with NK within 8 hours after endothelial injury, mural thrombi were histologically observed at the site of endothelial injury. In the control group, the center of vessel lumen was reopened and mural thrombi were attached on the surface of vessel walls. In contrast, in NK-treated groups, thrombi near the vessel wall showed lysis and most of them detached from the surface of vessel walls. In conclusion, dietary natto-extracts supplementation suppressed intimal thickening produced by endothelial injury in rat femoral artery. These effects may partially be attributable to NK, which showed enhanced thrombolysis near the vessel wall.

PMID: 12850244 [PubMed - indexed for MEDLINE]
link


1: Surgery. 2003 Aug;134(2):365-71. Links
P-selectin inhibition decreases post-thrombotic vein wall fibrosis in a rat model.Thanaporn P, Myers DD, Wrobleski SK, Hawley AE, Farris DM, Wakefield TW, Henke PK.
Section of Vascular Surgery, Department of Surgery, Jobst Vascular Laboratory and Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

BACKGROUND: Post-deep vein thrombosis (DVT) venous insufficiency is a vexing problem despite effective anticoagulation, and is characterized by vein wall fibrosis. This study tested the hypothesis that P-selectin inhibition would decrease post-thrombotic vein wall fibrosis and associated profibrotic mediators. METHODS: A rat stasis model of DVT was used to produce a 2-day-old DVT. Rats then received either intravenous saline (control), rPSGL-Ig (4 mg/kg) once, or daily subcutaneous low molecular weight heparin (LMWH) (0.5 mg/kg). Inferior vena cava wall was harvested 7 days after treatment and processed for thrombus size; leukocyte content; profibrotic mediators by enzyme-linked immunosorbent assay; collagen I and III mRNA expression by semiquantitative real-time polymerase chain reaction; and for collagen protein. RESULTS: Thrombus mass and leukocyte counts were similar between the groups. Treatment with rPSGL-Ig and LMWH resulted in less vein wall collagen (P <.05). rPSGL-Ig treatment (and a similar trend for LMWH) was associated with decreased profibrotic mediators, including less IL-13, MCP-1, bFGH, and transforming growth factor-beta (P <.05). Collagen III gene expression, but not collagen I gene expression, was increased with LMWH treatment (P <.05). CONCLUSIONS: P-selectin inhibition with rPSGL-Ig or LMWH decreases post-DVT vein wall fibrosis, and is associated with decreased vein wall profibrotic mediators. This effect is independent of thrombus mass and vein wall leukocytes.

PMID: 12947342 [PubMed - indexed for MEDLINE
link
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,
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Ellagic acid/walnut/pomegranate

Postby gibbledygook » Tue Feb 17, 2009 9:33 am

1: Br J Nutr. 2008 Apr;99(4):715-22. Epub 2007 Oct 5. Links
Walnut extract (Juglans regia L.) and its component ellagic acid exhibit anti-inflammatory activity in human aorta endothelial cells and osteoblastic activity in the cell line KS483.Papoutsi Z, Kassi E, Chinou I, Halabalaki M, Skaltsounis LA, Moutsatsou P.
Department of Biological Chemistry, Medical School, University of Athens, 75 Mikras Asias Street, Goudi 11527, Athens, Greece.

Epidemiological studies suggest that the incidence of CVD and postmenopausal osteoporosis is low in the Mediterranean area, where herbs and nuts, among others, play an important role in nutrition. In the present study, we sought a role of walnuts (Juglans regia L.) in endothelial and bone-cell function. As the endothelial cell expression of adhesion molecules has been recognised as an early step in inflammation and atherogenesis, we examined the effect of walnut methanolic extract and ellagic acid, one of its major polyphenolic components (as shown by HPLC analysis), on the expression of vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1 in human aortic endothelial cells. After incubating the cells with TNF-alpha (1 ng/ml) in the absence and in the presence of walnut extract (10-200 microg/ml) or ellagic acid (10- 7-10- 5 m), the VCAM-1 and ICAM-1 expression was quantified by cell-ELISA. We further evaluated the effect of walnut extract (10-50 microg/ml), in comparison with ellagic acid (10- 9-10- 6m), on nodule formation in the osteoblastic cell line KS483.Walnut extract and ellagic acid decreased significantly the TNF-alpha-induced endothelial expression of both VCAM-1 and ICAM-1 (P < 0.01; P < 0.001). Both walnut extract (at 10-25 microg/ml) and ellagic acid (at 10- 9-10- 8 m) induced nodule formation in KS483 osteoblasts. The present results suggest that the walnut extract has a high anti-atherogenic potential and a remarkable osteoblastic activity, an effect mediated, at least in part, by its major component ellagic acid. Such findings implicate the beneficial effect of a walnut-enriched diet on cardioprotection and bone loss.

PMID: 17916277 [PubMed - indexed for MEDLINE]
link


1: Br J Nutr. 2007 Apr;97(4):692-8. Links
Ellagic acid inhibits IL-1beta-induced cell adhesion molecule expression in human umbilical vein endothelial cells.Yu YM, Wang ZH, Liu CH, Chen CS.
Department of Nutrition, China Medical University, 91, Hsueh-Shih Road, Taichung, Taiwan. ymyu@mail.cmu.edu.tw

Expression of cell adhesion molecules by endothelium and the attachment of monocytes to endothelium may play a major role in atherosclerosis. Ellagic acid (EA) is a phenolic compound found in fruits and nuts including raspberries, strawberries, grapes and walnuts. Previous studies have indicated that EA possesses antioxidant activity in vitro. In the present study, we investigated the effects of EA on the formation of intracellular reactive oxygen species, the translocation of NFkappaB and expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 and endothelial leucocyte adhesion molecule (E-selectin) induced by IL-1beta in human umbilical vein endothelial cells (HUVEC). We found that EA significantly reduced the binding of human monocytic cell line, U937, to IL-1beta-treated HUVEC. The production of reactive oxygen species by IL-1beta was dose-dependently suppressed by EA. Supplementation with increasing doses of EA up to 50 micromol/l was most effective in inhibiting the expression of VCAM-1 and E-selectin. Furthermore, the inhibition of IL-1beta-induced adhesion molecule expression by EA was manifested by the suppression of nuclear translocation of p65 and p50. In conclusion, EA inhibits IL-1beta-induced nuclear translocation of p65 and p50, thereby suppressing the expression of VCAM-1 and E-selectin, resulting in decreased monocyte adhesion. Thus, EA has anti-inflammatory properties and may play an important role in the prevention of atherosclerosis.

PMID: 17349082 [PubMed - indexed for MEDLINE]
link


1: Anticancer Res. 2006 Sep-Oct;26(5A):3601-6.Links
Antioxidant and apoptosis-inducing activities of ellagic acid.Han DH, Lee MJ, Kim JH.
Department of Biochemistry, College of Dentistry, Kyung Hee University, Seoul 130-701, Korea.

BACKGROUND: Antioxidant, antiproliferative and apoptosis inducing activities of a natural polyphenolic compound, ellagic acid, were studied. MATERIALS AND METHODS: DPPH radical scavenging and lipid peroxidation inhibitory activities were observed. Activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were measured in ellagic acid-treated V79-4 cells. For apoptotic inducing activity, human osteogenic sarcoma (HOS) cell proliferation, chromosomal DNA degradation and changes in apoptosis-related protein levels were measured. RESULTS: Ellagic acid showed high DPPH radical scavenging and lipid peroxidation inhibition activities. SOD, CAT and GPX activities were significantly increased in ellagic acid-treated V79-4 cells. Ellagic acid significantly reduced HOS cell proliferation, and induced apoptosis evidenced by chromosomal DNA degradation and apoptotic body appearance. Bax expression was induced and caspase-3 was activated by ellagic acid treatment. CONCLUSION: Ellagic acid exhibited both antioxidant activity in V79-4 cells and apoptosis-inducing activity in HOS cells through the up-regulation of Bax and activation of caspase-3.

PMID: 17094489 [PubMed - indexed for MEDLINE]
link


1: Carcinogenesis. 2005 Apr;26(4):821-6. Epub 2005 Jan 20. Links
Combined inhibition of PDGF and VEGF receptors by ellagic acid, a dietary-derived phenolic compound.Labrecque L, Lamy S, Chapus A, Mihoubi S, Durocher Y, Cass B, Bojanowski MW, Gingras D, Béliveau R.
Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-Université du Québec à Montréal, Centre de Cancérologie Charles-Bruneau, 3175 Chemin Côte-Ste-Catherine, Montréal, Québec, Canada H3T 1C5.

The vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors play essential and complementary roles in angiogenesis and combined inhibition of these receptors has been shown to result in potent antitumor activity in vivo. In this study, we report that ellagic acid (EA), a natural polyphenol found in fruits and nuts, inhibits VEGF-induced phosphorylation of VEGFR-2 in endothelial cell (EC) as well as PDGF-induced phosphorylation of PDGFR in smooth muscle cells, leading to the inhibition of downstream signaling triggered by these receptors. EA also specifically inhibited VEGF-induced migration of ECs as well as their differentiation into capillary-like tubular structures and abolished PDGF-dependent smooth muscle cell migration. Interestingly, EA presents a greater selectivity for normal cells than for tumor cells since the migration of the U87 and HT1080 cell lines were much less affected by this molecule. The identification of EA as a naturally occurring dual inhibitor of VEGF and PDGF receptors suggests that this molecule possesses important antiangiogenic properties that may be helpful for the prevention and treatment of cancer.

PMID: 15661805 [PubMed - indexed for MEDLINE]
link
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,
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Postby gibbledygook » Sun Feb 22, 2009 2:33 am

This looks like Zamboni again.
1: J Vasc Surg. 1998 Nov;28(5):855-61. Links
Effects of vasoactive agents in healthy and diseased human saphenous veins.Rizzi A, Quaglio D, Vasquez G, Mascoli F, Amadesi S, Calò G, Regoli D, Zamboni P.
Department of Surgery, Institute of General Surgery and Section of Vascular Surgery, and the Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Italy.

PURPOSE: Smooth muscle reactivity is one of the factors involved in the pathogenesis of varicose veins. We investigated the myotropic effects of the 3 main vasoconstrictor agents norepinephrine (NE), angiotensin II (Ang II), and endothelin-1 (ET-1) in isolated human saphenous veins. METHODS: Human saphenous veins were collected from 23 patients with primary chronic venous insufficiency who underwent elective varicose vein resections and who were stratified into the following 3 groups: group 1, 7 patients in clinical class 2; group 2, 9 patients in clinical classes 3 and 4; and group 3, 7 patients in clinical classes 5 and 6. Moreover, 6 patients who underwent arterial bypass grafting procedures represented the control group. The tissues were suspended in organ baths that contained Krebs solution, and their mechanical responses were measured isometrically. The cumulative concentration-response curves to Ang II, NE, and ET-1 were performed at 90-minute intervals in each tissue. RESULTS: In the control tissues, NE, Ang II, and ET-1 induced concentration-dependent contractions with apparent affinities (pEC50, the negative logarithm to base 10 of the molar concentration of the agonist, which produces the 50% of the maximal effect) and maximal effects (maximum effect, g of contraction) that were equal to 7.06 +/- 0.23, 8.53 +/- 0.34, 7.63 +/- 0.10, and 2.21 +/- 0.33, 1.65 +/- 0.31, 2.60 +/- 0.77, respectively. Two main findings were evident in comparison of varicose veins with control tissues. First, the maximum effect that was evoked by all of the stimulants was reduced progressively with the increasing severity of the disease, which raised the third group to statistical significance for both NE and Ang II (P <.05). Second, a marked reduction of Ang II apparent affinity was already evident in tissues that were taken from patients in an early stage of the disease (P <.05). CONCLUSION: The demonstration of a significant reduction in Ang II and NE contractile activities and the important reduction of that of ET-1 in the diseased veins as compared with the control tissues extends the previous observations regarding the impairment of smooth muscle contractility in primary chronic venous insufficiency. Moreover, the dramatic reduction of Ang II affinity, which appears in an early stage of the disease, supports the hypothesis that such abnormality within the venous wall could play a role in the pathogenesis of primary varicose vein disease.

PMID: 9808853 [PubMed - indexed for MEDLINE]
link

I am once again trying butcher's broom (which I believe is slightly milder than horsechestnut) in combination with salvia and broccoli sprouts, curcumin, scutellaria, inosine etc.

I am perplexed by recent negative experiences on broccoli sprouts after alcohol usage. On a recent Friday night I had maybe a bottle of red wine. The following day I took 2 broccoli sprout pills in the am with a quercetin and about an hour later my leg was much stiffer walking than when I had first risen. The same happened yesterday. Yet when I take broccoli sprouts without any alcohol on the preceding day/night my leg usually feels a bit bouncier or more flexible after about an hour of consumption. I have noticed this also with salvia; the day after a night of alcohol is a bad day to take salvia and now also broccoli sprouts. Yesterday not only was my leg much stiffer after the broccoli sprouts but I also started getting quite a bit of tingling in my left knee which I haven't had for a while so I tried 500mg butcher's broom and it seemed to calm down a little bit but that may well be psychosomatic.

The above research suggests that our veins are not responding very well to the vasoconstrictors, of which endothelin 1 is highly overexpressed in MS patients. Butcher's broom (and horsechesnut) is said to increase venous tone...
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,
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Postby cheerleader » Sun Feb 22, 2009 10:22 am

Keep going, Alex!
AC
Last edited by cheerleader on Sun Feb 22, 2009 1:01 pm, edited 1 time in total.
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby gibbledygook » Sun Feb 22, 2009 12:35 pm

Thanks Cheereo!

I agree. It's very annoying!

Here's a more general piece about CVI. Interesting how microvessels are controlled by hormones and the adrenergic system...


1: Presse Med. 1994 Feb 10;23(5):213-24.Links
[Microcirculation and rheology][Article in French]


Barbier A, Boisseau MR, Braquet P, Carpentier P, Clostre F, Ladure P, Taccoen A.
Sanofi Recherche, Montpellier.

Microvessels, especially in the skin and muscles are organized in functional units. These units are controlled by the adrenergic system and hormones but also have autonomous metabolic and myogenic regulatory systems independent of vasomotion. Microcirculatory blood flow is affected by special rheologic properties: a low arteriolar haematocrit rises to the systemic level in the venules. The flow rate in the venules is low, and together with the raised haematocrit, explains the microvenular sensitivity to hyperviscosity. Capillarovenular microangiopathy, recently described by standard and fluorescent capillaroscopy, develops during chronic venous insufficiency. The capillary loops appear dilated and knotted together with fibrous deposits and pericapillary oedema. Venous hyperpressure is the cause of this microangiopathy. Together these phenomena disrupt normal haemodynamics and physiology of the microcirculatory unit: baseline hyperhaemia, lowered vasomotor and vasomotion reactivity, development of rheologic disorders (haemoconcentration, hyperfibrinogenaemia, erythrocyte agregation) and decreased fibrinolysis. Modifications in the transcapillary exchange is related to hypoxia and is aggravated by depressed lymphatic drainage. The main consequence is oedema. Inflammation, a characteristic of these microangiopathies could occur when the endothelium is activated by the hypoxia. The classical mediators of inflammation would activate interactions between the different cells: endothelium, granulocytes, monocytes and platelets. Several pharmacological models have been developed for the analysis of these data including exploration of the permeability and capillary resistance and rheological analysis. Objective observation of the microangiopathy with capillaroscopy, together with modern haemodynamical, biological and pharmacological methods are essential for a better understanding of microvascular disorders in chronic venous insufficiency.

PMID: 8177870 [PubMed - indexed for MEDLINE]
link


I'm back on butcher's broom which seems to me milder than horsechestnut. Here is something on their differences:


1: Arch Pharm (Weinheim). 1995 Oct;328(10):720-4.Links
Anti-elastase and anti-hyaluronidase activities of saponins and sapogenins from Hedera helix, Aesculus hippocastanum, and Ruscus aculeatus: factors contributing to their efficacy in the treatment of venous insufficiency.Facino RM, Carini M, Stefani R, Aldini G, Saibene L.
Istituto Chimico Farmaceutico Tossicologico, Faculty of Pharmacy, University of Milan, Italy.

Triterpene and steroid saponins and sapogenins of medicinal plants (Aesculus hippocastanum L., Hedera helix L., Ruscus aculeatus L.) are claimed to be effective for the treatment/prevention of venous insufficiency. In this work we evaluated the inhibitory effects of these plant constituents on the activity of elastase and hyaluronidase, the enzyme systems involved in the turnover of the main components of the perivascular amorphous substance. The results evidence that for Hedera helix L., the sapogenins only non-competitively inhibit hyaluronidase activity in a dose-dependent fashion, showing comparable IC50 values (hederagenin IC50 = 280.4 microM; oleanolic acid IC50 = 300.2 microM); both the saponins hederacoside C and alpha-hederin are very weak inhibitors. The same behaviour is observed for serine protease porcine pancreatic elastase: the glycosides are devoid of inhibitory action, while genins are potent competitive inhibitors (oleanolic acid IC50 = 5.1 microM; hederagenin IC50 = 40.6 microM). Constituents from Aesculus hippocastanum L. show inhibitory effects only on hyaluronidase, and this activity is mainly linked to the saponin escin (IC50 = 149.9 microM), less to its genin escinol (IC50 = 1.65 mM). By contrast, ruscogenins from Ruscus aculeatus L., ineffective on hyaluronidase activity, exhibit remarkable anti-elastase activity (IC50 = 119.9 microM; competitive inhibition). The mechanism of elastase inhibition by triterpene and steroid aglycones, with a nitroanilide derivative as substrate, is discussed.

PMID: 8554461 [PubMed - indexed for MEDLINE]
link

elastase according to wikipedia:

In molecular biology, elastase is an enzyme from the class of proteases (peptidases), that break down proteins.

Elastase breaks down elastin, an elastic fibre that, together with collagen, determines the mechanical properties of connective tissue. The neutrophil form breaks down the Outer membrane protein A (OmpA) of E. coli and other Gram-negative bacteria, and also breaks down Shigella virulence factors. This is accomplished through the cleavage of peptide bonds in the target proteins. The specific peptide bonds cleaved are those on the carboxy side of small, hydrophobic amino acids such as glycine, alanine, and valine. For more on how this is accomplished, see serine protease....

Elastase has been shown to disrupt tight junctions, cause proteolytic damage to tissue, break down cytokines and alpha proteinase inhibitor, cleave immunoglobuline A and G (IgA, IgG), and cleave both C3bi, a component of the complement system, and CR1, a receptor on neutrophils for another complement molecule involved in phagocytosis. The cleavage of IgA, IgG, C3bi, and CR1 contributes to a decrease of the ability of neutrophils to kill bacteria by phagocytosis. Together all these factors contribute to human pathology.



now I'm sure elastin came into some research I did earlier. Will have to hunt around a bit...

1: Histol Histopathol. 2008 Feb;23(2):179-86. Links
Down-regulation of lysyl oxydase-like in aging and venous insufficiency.Pascual G, Mendieta C, Mecham RP, Sommer P, Bellón JM, Buján J.
Department of Medical Specialities, Networking Research Center on Biomaterials and Nanomedicine (CIBER-BBN), Alcalá de Henares, Madrid, Spain.

BACKGROUND: Elastin expression is higher in tissues where elastic fibres are essential for the correct maintenance of function such as blood vessels. Elastin expression usually diminishes with age, however, it may be re-expressed in response to injury or repair processes. Some authors attribute the characteristic loss of elasticity of the varicose vein to a drop in the population of smooth muscle cells in the media layer. A reduction in elastin has been observed in chronic venous insufficiency, but little is known about some of the factors involved in elastin synthesis such as lysyl oxidases. The aim of this study was to examine the in vivo expression of the elastin precursor, tropoelastin (TE), and lysyl oxidase-like 1 (LOXL1), a cross-linking enzyme responsible for elastin polymer deposition. The effects of age on these expression patterns were also evaluated. METHODS: Saphenous vein segments were obtained during surgery from organ donors (controls, n=20) and subjects with venous insufficiency (varicose veins, n=20). Both these groups were subdivided according to subject age into <50 years (n=10) and >or=50 years (n=10). Control and varicose vein tissue specimens were immunolabelled using anti-tropoelastin and anti-LOXL1 antibodies and also subjected to Western blot analysis. RESULTS: Our results indicate that the levels of these markers of elastin synthesis (LOXL/tropoelastin) in the vein wall diminish in a significant way (p<0.05) with the age factor. Excluding the age factor, LOXL1 was significantly decreased in the varicose condition (p<0.05). In the younger pathological population they showed an inverse relationship (LOXL decreased, tropoelastin increased). CONCLUSIONS: The already established reduction in elastin in the varicose condition may be related, at least in part, to the decreased LOXL1 levels observed here. These events could reduce spontaneous reticulation of elastin and the partial loss of tissue elasticity in this group of patients.

PMID: 17999374 [PubMed - indexed for MEDLINE]
link[/quote]
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Elastase

Postby LR1234 » Sun Feb 22, 2009 2:49 pm

Hi Alex,
I don't know that much about elastase but I know that when it was thought that I had CFS/ME for 13 years my levels were tested by a Dr in Brussels and it was way too high. This is one of the things he follows to monitor the CFS/ME's response to treatment.

On my last blood tests it said "high leucocyte elastase activity" (I think elastase breaks down elastin or something like that)

(I haven't been tested again since my MS diagnosis)

Leanne
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Postby gibbledygook » Tue Feb 24, 2009 10:07 am

Hi L,

How interesting. Yes, elastase (like many enzymes ending in - ase) breaks down elastin which keeps the veins/blood vessels in good shape. In MS the veins show both excessive distension and excessive narrowings with the vessel become very tortuous and twisted in the narrow sections. This leads to blood flowing back the wrong way, much as in chronic venous insufficiency of the legs. Reducing elastase might be good as that might lead to less distension. On the other hand the narrow sections might benefit from less elastin. I still haven't ascertained what causes the veins to become narrow and tortuous. That would be very helpful information!

Here's something else on butcher's broom:


1: J Vasc Surg. 1999 Nov;30(5):876-83. Links
Cyclic nucleotides and production of prostanoids in human varicose veins.Nemcova S, Gloviczki P, Rud KS, Miller VM.
Division of Vascular Surgery, Department of Surgery, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

OBJECTIVE: Experiments were designed to determine the production of prostacyclin and thromboxane and the activation of cyclic nucleotides in human varicose and nonvaricose veins and to determine whether these second messenger pathways were differentially activated by the venotropic extract of Ruscus aculeatus. METHODS: The experiments were designed to characterize the activity of cyclic nucleotides and the production of prostaglandins in human varicose and nonvaricose veins. Segments of the greater saphenous veins and the adjacent tributaries were obtained from patients who underwent vein stripping and excision of primary varicose veins. The saphenous veins from the patients who underwent peripheral arterial bypass grafting were used as controls. The segments of veins were incubated in Krebs-Ringer bicarbonate solution in the presence of venotropic extract of Ruscus aculeatus (10(-3) g/mL) or in water-miscible organic solvent (dimethyl sulfoxide, 10(-3) g/mL), for 1, 5, and 10 minutes at 37 degrees C. The nonspecific phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, 10(-4) g/mL) was used to block cyclic nucleotide degradation in some samples. Tissue and media samples were collected. Tissue concentrations of both cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP and cGMP, respectively) and media concentrations of 6-ketoprostaglandin-F(1)(alpha) (the stable metabolite of prostacyclin) and thromboxane B(2) (the stable metabolite of thromboxane A(2)) were measured by means of radioimmunoassay. Cyclooxygenase 2 was measured with Western blot analysis. RESULTS: The varicose veins showed greater levels of cAMP but not of cGMP at all time points as compared with the control veins. Prostanoid production was not significantly altered in the varicose veins. Stimulation with Ruscus aculeatus increased the cAMP concentration in the varicose veins but did not affect the cGMP levels. The ratio between 6-ketoprostaglandin-F(1)(alpha) and thromboxane B(2) was two-fold greater in the varicose veins as compared with the control veins. In the presence of the extract, the ratio of 6-ketoprostaglandin-F(1)(alpha) and thromboxane B(2) was identical in both types of veins. Cyclooxygenase 2 was not present in either the control or the varicose veins. CONCLUSION: These results suggest that cAMP levels are elevated in varicose veins and that they can be altered with drug treatment in varicose veins. This chemical pathway may be considered as a modulatory target to affect contraction with venotropic drugs.

PMID: 10550185 [PubMed - indexed for MEDLINE]
link

The reduction in this ratio might reduce vasodilation.


Elastin mentioned here:

1: J Cardiovasc Pharmacol. 2008 Jul;52(1):55-65.Links
Plant-derived micronutrients suppress monocyte adhesion to cultured human aortic endothelial cell layer by modulating its extracellular matrix composition.Ivanov V, Ivanova S, Kalinovsky T, Niedzwiecki A, Rath M.
Dr. Rath Research Institute, Santa Clara, California, USA.

Monocyte adhesion to endothelium plays an important role in atherosclerosis. We investigated the effects of micronutrients on monocyte-binding properties of extracellular matrix (ECM) produced by human aortic endothelial cells (AoEC). Confluent cultures of AoEC were exposed to ascorbic acid, quercetin, gotu kola extract (10% asiatic acid), green tea extract (40% epigallocatechin gallate), or a mixture of these micronutrients for 48 hours. AoEC-produced ECM was exposed by differential treatment. U937 monocyte adhesion was assayed by fluorescence. ECM composition was assayed immunochemically and with radiolabeled metabolic precursors. AoEC exposure to micronutrients reduced ECM capacity to bind monocytes in a dose-dependent manner. This effect was accompanied by profound changes in the ECM composition. Correlation analysis revealed that changes in monocyte adhesion to ECM had the strongest positive correlation with ECM content for laminin (CC = 0.9681, P < 0.01), followed by fibronectin, collagens type III, I, and IV, biglycan, heparan sulfate, and elastin. The strongest negative correlation was with chondroitin sulfate (CC = -0.9623, P < 0.01), followed by perlecan and versican. Individual micronutrients had diverse effects on ECM composition and binding properties, and their mixture was the most effective treatment. In conclusion, micronutrient-dependent reduction of monocyte adhesion to endothelium is partly mediated through specific modulation of ECM composition and properties.

PMID: 18594473 [PubMed - indexed for MEDLINE]



THIS LOOKS PROMISING! I wonder if it would work by consuming an extract of dill, I wonder if Iherb do dill!

: Exp Dermatol. 2006 Aug;15(8):574-81. Links
LOXL as a target to increase the elastin content in adult skin: a dill extract induces the LOXL gene expression.Cenizo V, André V, Reymermier C, Sommer P, Damour O, Perrier E.
Laboratoire des Substituts Cutanés, Hôpital E. Herriot, Lyon, France.

The lysyl oxidases lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) are responsible for elastin cross-linking. It was shown recently that LOXL is essential for the elastic fibres homeostasis and for their maintenance at adult age. We first determined whether or not elastin, LOX and LOXL are less expressed during adulthood. The LOX and LOXL mRNA level, quantified by real-time reverse transcriptase-polymerase chain reaction decreased in adult skin fibroblasts compared with fibroblasts from children. In contrast, the elastin mRNA level remains stable at all ages. The goal of this study was to induce elastogenesis at the adult age. Therefore, both enzymes, and in particular LOXL, of which expression is the most affected by age, could be targeted to induce elastogenesis in adult skin. We screened a library of about 1000 active ingredients to find activators capable to stimulate specifically the LOXL gene expression in adult dermal fibroblasts. The positive effect of selected active ingredients was confirmed on fibroblasts grown on monolayers and on dermal and skin equivalent cultures. One extract, obtained from dill (LYS'LASTINE V, Engelhard, Lyon, France), stimulates the LOXL gene expression in dermal equivalents (+64% increase in the LOXL mRNA level when compared with control). At the same time, the elastin detection is increased in dermal equivalents and under the dermal-epidermal junction of skin equivalents, without increase of the elastin mRNA. In conclusion, LOXL can be considered as a new target to reinduce elastogenesis. Its stimulation by a dill extract is correlated with increased elastin detection, suggesting an increase in elastogenesis efficiency.

PMID: 16842595 [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,
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gibbledygook
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Postby gibbledygook » Wed Feb 25, 2009 9:57 am

I've just been for a walk and managed 500meters around the block but could do no further which is somehow rather disappointing as I had managed 1.1km before Christmas. I have just spent one week taking 1g of butcher's broom daily with 2 broccoli sprout pills and either quercetin, salvia or ginkgo and curcumin etc. Today I took 120mg gingko. So this begs the question, is the butcher's broom counterproductive? Or have I still not fully recovered from my Christmas relapse induced by superoxide dismutase? Ho hum. Time to play around with the combinations of ginkgo/broccoli sprouts/salvia/quercetin/butcher's broom.

Am going to log my walking per day here, I shall not include curcumin, scutellaria etc as I am assuming that they only exert mild benefits and are not principally active in the vasculature as are butcher's broom, horsechestnut, salvia, ginkgo, quercetin and broccolli sprouts. I will also repeat the dosages at lunch and night time.

25/2/09 120mg ginkgo, 1 Life extension broc sprout, 1 source natural broc sprout, 500mg butcher's broom, 600mg hesperidin = 500m, uncomfortable, foot pick-up poor, tingling in left knee post-walk
Start sleeping on a 6inch inclined bed.

26/2/09 500mg butcher's broom, 600mg hesperidin = 500m, much more comfortable than yesterday, pick-up okay, no tingling post-walk

27/2/09 600mg horsechestnut, 600mg hesperidin = 500m, less comfortable than 26/2/09, less pick-up but minor tingling post-walk, better than 25/2/09

2/3/09 500mg butcher's broom, 600mg hesperidin, 333mg quercetin, good 500m with very little post-walk tingle. Walked with good bounce/lift-off

3/3/09 500mg butcher's broom, 600mg hesperidin, 666mg quercetin. Good 500m walk, much like 2/3/09 but perhaps with more give (positive) or bounce in the pace, negligible post-walk tingle

4/3/09 600mg horsechestnut, 600mg hesperidin, 333mg quercetin. Manage a good 900m walk in unfamiliar busy streets before flagging a cab. Great given had drunk 3/4 bottle red wine previous night.

6/3/09 600mg horsechestnut, 600mg hesperidin, 666mg quercetin. Walk much less good than 4/3/09, though manage 500m, no post walk tingle. Drank 2/3 bottle red wine previous night.

weekend 7/3 - 8/3 away, pain in left foot starts to appear, same as old burning sensation of time before dilators taken in quantity last year

9/3/09 600mg horsechestnut, 600mg hesperidin, 666mg quercetin. Walk still not as good as 4/3/09, manage 500m, little post-walk tingle.

10/3/09 600mg horsechestnut, 600mg hesperidin, 500mg butcher's broom, 333mg quercetin. Walk 500m, little post walk tingle, not as good as 4/3/09. Walking different to yesterday, not sure if better or worse. No night spasms, no leg pain after same dose at 17:00.

11/3/09 600mg horsechestnut, 600mg hesperidin, 500mg butcher's broom. Walk 900m, less post walk tingle than yesterday, started with a good bounce in the bad foot, gets a bit tricky around 600m. Nearly as good as 4/3/09.

12/3/09 600mg horsechestnut, 600mg hesperidin, 500mg butcher's broom, 300mg aspirin. (using aspirin for anti-platelet activity but also now see that it is a dilator, mmm) Walk 600m with good bounce initially, much like yesterday, much more tingling post walk.


16/3/09 1.2g horsechestnut, 600mg hesperidin, 500mg butcher's broom, 333mg quercetin. Can only just manage 700m and plenty of tingling a lot on earlier walk but not so much on 2nd walk. Pick-up poor. Pain in left foot appears more severely than other days. Consequently, take 1050mg salvia and 666mg quercetin through rest of day, pain ameliorates. Terrible night, bad sleep, spasms.

17/3/09 600mg horsechestnut, 500mg butcher's broom, 600mg hesperidin, 600mg salvia. Manage 900m, much better than yesterday but not as good as 4/3/09. Hardly any post-walk tingling. Tricky from 600m. Not as good as 11/3/9.

18/3/9 333mg quercetin. Manage a 900m, initially better than yesterday, 17.3.9, need toilet towards end (this always is bad for my walking ability) and walking then much worse, less pick-up than yesterday in last 200m. Hardly any post-walk tingling. So far, midday, no pain in left foot toes, whereas yesterday and day before I had this pain in the am.

19/3/09
500mg butcher's broom, 120mg ginkgo biloba. Manage 900m but less good than 18/3/09 and with toilet urgency towards. Think must come off all vasoactive herbs for two days. pain in left foot subdued.

20/3/09
No vasoactive herbs but plenty curcumin etc. Am going to enjoy some wine tonight too. Maybe some pyschoactive herbs instead too! FRIDAY feeling. :lol:

22/23/3/09
spent weekend taking vasodilatory salvia and quercetin which seem to alleviate the pain in my left foot which developed whilst on the horsechestnut/bucher's broom experiment. However suffer from severe left foot pain in am both mornings, Right leg (with motor dysfunction) becomes very spongy. Don't attempt any long walks

23/3/09
Pain in left foot in am milder than before. Right leg very spongy in am before dilators. Resolve to reduce dilators as far as possible today. Pain returns by mid-morning and 333mg quercetin doesn't help so take 525mg of salvia and an hour later pain is down! Extraordinary. Can't be bothered going for walk today as it's all cloudy and rainy. Pain returns so go for 1020mg salvia and after a bit, pain is back down again and walking not much different to am. Yesterday I took in total about 2g salvia. Today will aim for 3g. Think it was a mistake trying to come off the dilators this am. Pouring with rain now.
In the end take only just over 2g of salvia and this is quite enough to make right leg quite spongy and bladder a bit poorer so no more than 2g to be consumed with veins in current state.

24/3/09
Pain in am in left foot is better though still perceptible. Right foot also quite spongy so try to avoid salvia for as long as possible today and focus on curcumin, inosine etc. It occurred to me that the capsaicin was also not helping when vein wall has been breached and so am not going to take any until vein wall feels healed up and will use senokot to keep regular. It's already 11am and the pain in left foot has been very quiet today. Will take 510mg of salvia if and when it arises but no more than 1.5g. Fly to Cape Town on Friday so must get legs working again. Knowledge of how these vasoactive herbs work is becoming increasingly useful. :lol: Managed whole day sin salvia. Good.

25/3/09
It's clear I've had a small relapse affecting both the left foot and to a lesser extent the right foot. I still have the burning pain in the left foot in the am and a rather stiffer than before right foot on rising. Today I add some lumbrokinase and nattokinase to break up the fibrin being deposited on the damaged nerves. However the whole day my left foot has been blighted with pain in the toe area even after 333mg of quercetin and plenty of curcumin, inosine, scutellaria. At 16:00 I take 1.2g of berberine. At 18:00 the pain feels gone! I take also at 17:35 one life extension broccoli sprouts as I'm going slightly around the bend trying to work out what combination could help in time for Friday. Looks like I may have hit on it!

26/3/09
I take 1.8g berberine in the am and 1.2g every four hours and 1.8g at night and I suffer virtually no pain, however as with other dilators this negatively affects my walking. I also get bad spasms for a while after the night dose.
27/3/09
I take 1.8g berberine at 6.30 and 1.2g at 10:30. At 11:00 I walk pretty poorly with bad pick-up but little stiffness. I suffer very little pain even though I can tell there is damage when I stand in the am. Will back off the dosages now especially as today I have to brave the airport this pm. Maybe 600mg ever 4 hours? However as dilators go, this is much milder, I think, than salvia or ginkgo.

19/4/09
Back from Africa where it was clear that I had suffered a relapse and that berberine was really helpful. For the first time since becoming ill with MS I suffered NO spasms on the long-haul flight on quite a lot of berberine. I also noticed that I suffered no spasms throughout my holiday until I started coming down with tick bite fever which lasted about 10days and was only cleared with doxicycline. The berberine has some very impressive properties however I am still more disabled than I was a month ago. I believe that the horsechestnut and butcher's broom tightened up the vein walls too much and then the sudden addition of large doses of salvia/ginkgo to stop the newly developed pain in the left foot caused a dramatic alteration in heamodynamics. I reckon that these vasoactive herbs should only be taken in small quantity and alterations gradually made. At present my left foot pain has gone and standing in the morning is mostly fine, my right foot and knee are much stiffer and feel as though there is a good deal of oedama. I am taking 600mg of berberine at night only and am starting my new chinese tea which is principally centenella asiatica and something called ilicis pubescentis radix with a bit of ginkgo, astragalus, angelica sinensis and peony.

21/4/09
Took 900mg gotu kola with 2g curcumin, 1.8g scutellaria and the usual vits. My walking is very poor and I can only manage about 50meters. I didn't even try the 500m circuit as I know my foot and leg are not up for it.


22/4/09
Today I stopped the gotu kola and the scutellaria as I saw that gotu kola contains quercetin and this probably explains my worse walking yesterday and the day before - never take dilators or vasoactive drugs during a relapse.

25/4/09
It is clear that I still have or have developed some infection that has been giving me a high temperature and also for the last two days sharp pains in my left jaw lymph node. Temperature has been up to 99.5. I have reduced radically the vasoactive herbs and am now mainly on curcumin and capsaicin, sometimes I throw in one horsechestnut or one butcher's broom per day in the am and one gotu kola at night. I still feel a change for the worse after taking the capsaicin and curcumin so then later sometimes take a horsechestnut to reduce oedama and dilation. However I now know never to take the horsechestnut/butcher's broom in even moderate dose without a dilator. I take the gotu kola at night because on the night I converted to just capsaicin/curcumin I had bad spasms. Nights with the gotu kola/berberine are much better.
On the whole, today I am finally feeling a little less feverish and the lymph nodes are quite a bit less sore.

I think maybe that this is still the tick bite fever as I simply cannot explain this fever without any other cold symptom apart from painful lymphs. This was exactly the symptom of tick bite fever and also the sharply reduced walking ability.


29/4/09
I have had no renewed lymph node pain and yet my temperature is constantly at 99 to 99.5. This seems to be impacting my walking which felt as spongy yesterday as if I'd been on lots of vasodilators and walking was tricky. Could only manage 100m around 4pm. I had on curcumin and capsaicin with no other herbs. Around 6pm I took some curcumin, 600mg horsechestnut and 1.8g capsaicin. This am the pain in my left toes reappeared having been virtually absent since mid-African trip. there is quite some correlation between this and horsechestnut! Today my walking seems much better though the temperature was once again 99 this am.



I have noticed before that if I have drunk alcohol, then the dilators such as quercetin, salvia or ginkgo need to be taken in minimal/reduced quantity.

19/3/09
The trend if there is one, seems to indicate that the vasodilators are BAD and the vasoconstrictors (horsechestnut, butcher's broom, hesperidin) are also bad! The dilators seem to make the walking more muffled/spongy and the bladder weaker whilst the constrictors seem to make the walking quite good and the bladder stronger but eventually cause pain. As I imagine, the constriction is initially good on the distended/permeable bits of the vein which lie along the lesion but then cause the stenoses to worsen and thus increase pressures on other vein segments...

I fear that vasoactive herbs, whilst occasionally potentially good, can never resolve the problem of the veins' configuration and how the CNS lesion develops alongside this: the lesion begins with the vein stenosis and runs back upstream as the vein becomes more distended. At least, this is how I understand it. In any event, these last few weeks have proven to me that the vasoconstrictive herbs aren't helpful except in the most modest quantities. Before Christmas I took plenty of vasodilatory herbs and these too weren't helpful at least in large quantity.
Having said that the herb salvia does seem to very good at reducing pain in my left foot and leg. It seems to be alleviating the burning pain which started on my recent horsechestnut/butcher's broom experiment and also vastly reduced the burning pain from last year when I went crazy taking loads and loads of the dilators! Mmm. 25/4/09 I subsequently discovered that berberine was more effective than salvia in reducing the pain from the newly developed lesion. Now my left foot is much much better and almost back to a month and half ago before this latest episode.
Last edited by gibbledygook on Wed Apr 29, 2009 2:50 am, edited 42 times in total.
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,
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