VEGF is upregulated in MS and may increase vascular permeability:
1: Life Sci. 2008 Sep 12;83(11-12):404-12. Epub 2008 Jul 30. Links
Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) inhibits experimental autoimmune encephalomyelitis in dark Agouti (DA) rats.Zhu CS, Hu XQ, Xiong ZJ, Lu ZQ, Zhou GY, Wang DJ.
Department of Neurology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, People's Republic of China.
Previous studies have shown that vascular endothelial growth factor (VEGF) expression is up-regulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a model for MS, and may exacerbate the disease. However, it remains unknown whether anti-VEGF modalities could serve as a potential treatment for such central nervous system (CNS) autoimmune diseases. We constructed a recombinant adenoviral vector carrying FLAG-tagged sFlt-1(1-3) (the first three extracellular domains of Flt-1, the hVEGF receptor-1). Intramuscular transfection of the recombinant adenoviral vector suppressed VEGF-induced inflammatory cell infiltration in matrigel plugs. When given intracerebrally to EAE rats, recombinant sFlt-1(1-3) adenoviral vector significantly reduced disease severity compared to untreated rats. sFlt-1(1-3) gene transfer blocked VEGF and greatly reduced the number of cells that express VEGF and ED1-positive cells in CNS in EAE rats. This study demonstrates that sFlt-1(1-3) gene transfer into the brain ameliorates the severity of EAE by inhibiting monocyte recruitment in the CNS of dark Agouti rats.
PMID: 18721816 [PubMed - in process]
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flavonoids inhibit vascular permeability/angiogenesis:
1: Pharmacol Res. 2008 Apr;57(4):259-65. Epub 2008 Feb 23. Links
Antiangiogenic effects of flavonoids and chalcones.Mojzis J, Varinska L, Mojzisova G, Kostova I, Mirossay L.
Department of Pharmacology, Faculty of Medicine, P.J. Safarik University, Trieda SNP 1, 04011 Kosice, Slovak Republic.
jan.mojzis@upjs.sk
Angiogenesis, the development of new blood vessels from the existing vasculature, is essential in normal developmental processes. Uncontrolled angiogenesis is a major contributor to a number of disease states such as inflammatory disorders, obesity, asthma, diabetes, cirrhosis, multiple sclerosis, endometriosis, AIDS, bacterial infections and autoimmune disease. It is also considered a key step in tumour growth, invasion, and metastasis. Angiogenesis is required for proper nourishment and removal of metabolic wastes from tumour sites. Therefore, modulation of angiogenesis is considered as therapeutic strategies of great importance for human health. Numerous bioactive plant compounds are recently tested for their antiangiogenic potential. Among the most frequently studied are polyphenols present in fruits and vegetables. Plant polyphenols inhibit angiogenesis and metastasis through regulation of multiple signalling pathways. Specifically, flavonoids and chalcones regulate expression of VEGF, matrix metalloproteinases (MMPs), EGFR and inhibit NFkappaB, PI3-K/Akt, ERK1/2 signalling pathways, thereby causing strong antiangiogenic effects. This review focuses on the antiangiogenic properties of flavonoids and chalcones and examines underlying mechanisms.
PMID: 18387817 [PubMed - indexed for MEDLINE]
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1: J Clin Immunol. 2007 May;27(3):246-56. Epub 2007 Mar 6. Links
Vascular endothelial growth factor (VEGF) in autoimmune diseases.Carvalho JF, Blank M, Shoenfeld Y.
Rheumatology Division, São Paulo University, School of Medicine, São Paulo, Brazil.
Vascular endothelial growth factor (VEGF) is a potent stimulating factor for angiogenesis and vascular permeability. There are eight isoforms with different and sometimes overlapping functions. The mechanisms of action are under investigation with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins, which were not previously associated to angiogenesis. VEGF has important physiological actions on embryonic development, healing, and menstrual cycle. It also has a great role in pathological conditions that are associated to autoimmune diseases. There is considerable evidence in various autoimmune diseases such as in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis of an interrelationship between the VEGF system and theses disorders. Serum levels of VEGF correlate with disease activity in a large number of autoimmune diseases and fall with the use of standard therapy. We raised the possible future therapeutic strategies in autoimmune diseases with the anti-VEGF or anti-VEGFR (receptor). So far, this therapy has been used in cancer and macular ocular degeneration in diabetes. This review outlines the evidence for VEGF participation in various autoimmune diseases and proposes lines for future research in this field.
PMID: 17340192 [PubMed - indexed for MEDLINE]
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1: Front Biosci. 2007 Jan 1;12:1615-28.Links
Corticotropin-releasing hormone and the blood-brain-barrier.Theoharides TC, Konstantinidou AD.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, 136 Harrison Avenue, Boston, MA 02111, USA.
theoharis.theoharides@tufts.edu
Increased blood-brain-barrier (BBB) permeability precedes any clinical or pathologic signs and is critical in the pathogenesis of multiple sclerosis (MS) and brain metastases. CD4+ TH1 cells mediate demyelination in MS, but how they get sensitized and enter the brain to induce brain inflammation remains obscure. TH2 cytokines associated with allergic disorders have recently been implicated in MS, while genes upregulated in MS plaques include the mast cell-specific tryptase, the IgE receptor (Fc-epsilon-RI) and the histamine-1 receptor. Mast cell specific tryptase is elevated in the CSF of MS patients, induces microvascular leakage and stimulates protease-activated receptors (PAR), leading to widespread inflammation. BBB permeability, MS and brain metastases appear to worsen in response to acute stress that leads to the local release of corticotropin-releasing hormone (CRH), which activates brain mast cells to selectively release IL-6, IL-8 and vascular endothelial growth factor (VEGF). Acute stress increases BBB permeability that is dependent on CRH and mast cells. Acute stress shortens the time of onset of experimental alleric encephalomyelitis (EAE) that does not develop in W/W mast cell deficient or CRH -/- mice. Brain mast cell inhibition and CRHR antagonists offer novel therapeutic possibilities.
PMID: 17127408 [PubMed - indexed for MEDLINE]
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1: J Immunol. 2006 Oct 15;177(8):5574-84. Links
IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program.Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR.
Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York, NY 10029, USA.
Loss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1beta, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1beta induced the expression of genes favoring vessel plasticity, including HIF-1alpha and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1alpha and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1beta in the brain induced astrocytic expression of HIF-1alpha, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1beta-induced HIF-1alpha in its regulation. These results suggest that IL-1beta contributes to BBB permeability in MS via reactivation of the HIF-VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.
PMID: 17015745 [PubMed - indexed for MEDLINE]
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This herb looks interesting:
1: Clin Cancer Res. 2004 Dec 15;10(24):8266-74. Links
Pseudolaric acid B inhibits angiogenesis and reduces hypoxia-inducible factor 1alpha by promoting proteasome-mediated degradation.Li MH, Miao ZH, Tan WF, Yue JM, Zhang C, Lin LP, Zhang XW, Ding J.
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
PURPOSE: Pseudolaric acid B (PAB), the naturally occurring diterpenoid isolated from the root bark of Pseudolarix kaempferi Gordon tree (Pinaceae), possesses potent antifungal and pregnancy-terminating effects that may be tightly associated with angiogenesis. This study was to examine its angiogenic inhibition, impact on vascular endothelial growth factor (VEGF) secretion from tumor cells and the possible mechanism of action. EXPERIMENTAL DESIGN: Angiogenesis inhibition was assessed by the human umbilical vascular endothelial cell proliferation, migration, and tube-formation assays, as well as the chorioallantoic membrane assay. ELISA, reverse transcription-PCR, and Western blotting analyses were performed to examine VEGF protein secretion, mRNA expression, and the possible mechanism in hypoxic MDA-MB-468 cells. RESULTS: PAB displayed potent in vitro antiangiogenic activity shown by inhibiting VEGF-stimulated proliferation and migration and fetal bovine serum-stimulated tube formation of human umbilical vascular endothelial cells in a concentration-dependent manner. Moreover, PAB (10 nmol per egg) significantly suppressed in vivo angiogenesis in the chorioallantoic membrane assay. On the other hand, PAB abrogated hypoxia-induced VEGF secretion from MDA-MB-468 cells via reducing HIF-1alpha protein. Additional analyses using LY294002 and U0126 indicated that the increase in hypoxia-inducible factor 1 (HIF-1)alpha protein level was highly dependent on phosphatidylinositol 3'-kinase and p42/p44 mitogen-activated protein kinase activities in hypoxic MDA-MB-468 cells. However, PAB treatment did not affect the active (phosphorylated) forms of Akt and Erk. Interestingly, the selective proteasome inhibitor MG-132 completely reversed the reduction of HIF-1alpha protein in the PAB-treated MDA-MB-468 cells. CONCLUSIONS: PAB displays the dual antiangiogenic activities of directly inhibiting endothelial cells and abrogating paracrine stimulation of VEGF from tumor cells due to reducing HIF-1alpha protein by promoting its proteasome-mediated degradation in MDA-MB-468 cells, which has potential clinical relevance.
PMID: 15623602 [PubMed - indexed for MEDLINE]
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as does hesperidin:
1: Mol Cell Biochem. 2007 Nov;305(1-2):153-61. Epub 2007 Jul 13. Links
Hesperidin inhibits expression of hypoxia inducible factor-1 alpha and inflammatory cytokine production from mast cells.Choi IY, Kim SJ, Jeong HJ, Park SH, Song YS, Lee JH, Kang TH, Park JH, Hwang GS, Lee EJ, Hong SH, Kim HM, Um JY.
College of Oriental Medicine, Institute of Oriental Medicine, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul, 130-701, Republic of Korea.
The citrus unshiu peel has been used traditionally as a medicine to improve bronchial and asthmatic conditions or cardiac and blood circulation in Korea, China, and Japan. Here, we report the effects of citrus unshiu peel water extract (CPWE) on the phorbol myristate acetate (PMA)+calcium ionophore A23187-induced hypoxia-inducible factor-1alpha (HIF-1alpha) activation and inflammatory cytokine production from the human mast cell line, HMC-1 cells. We compared CPWE with hesperidin, a common constituent of citrus unshiu. CPWE and hesperidin inhibited the PMA+A23187-induced HIF-1alpha expression and the subsequent production of vascular endothelial growth factor (VEGF). In addition, CPWE suppressed PMA+A23187-induced phosphorylation of the extracellular signal-regulated kinase (ERK). We also show that the increased cytokines interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha level was significantly inhibited by treatment of CPWE or hesperidin. In the present study, we report that CPWE and hesperidin are inhibitors of HIF-1alpha and cytokines on the mast cell-mediated inflammatory responses.
PMID: 17629775 [PubMed - indexed for MEDLINE]
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or dang gui:
1: Pathobiology. 2006;73(3):141-8. Links
Biological inhibitory effects of the Chinese herb danggui on brain astrocytoma.Lee WH, Jin JS, Tsai WC, Chen YT, Chang WL, Yao CW, Sheu LF, Chen A.
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
OBJECTIVE: Previous studies have demonstrated the utility of the traditional Chinese herb danggui in the treatment of chronic myelogenous leukemia. Our aim was to examine whether it might similarly be used to treat glioblastoma multiforme. METHODS: The lipid-soluble active ingredients of danggui were extracted with acetone (AS-AC) or chlorophenol (AS-CH) and their antiproliferative and proapoptotic effects were studiedin vitro on cultured GBM 8401 cells and in vivoon tumors in nude mice. RESULTS: After a 24-hour treatment, either AS-AC or AS-CH at a lower (50 micro g/ml) and a higher concentration (100 micro g/ml) significantly inhibited the proliferative activity of GBM 8401 cultured cells by 30-50%, as well as the expression of cathepsin B and vascular endothelial growth factor (VEGF). In nude mice, the growth of the tumor was inhibited by 30% by AS-CH or AS-AC (20 mg/kg; p < 0.05) and by 60% by AS-CH or AS-AC (60 mg/kg; p < 0.05). AS-AC and AS-CH also significantly inhibited microvessel formation in the tumors of nude mice. CONCLUSIONS: Danggui may inhibit tumor growth by reducing the level of VEGF and the proapoptotic protein, cathepsin B. Thus, danggui may be useful in the treatment of high-grade astrocytomas.
PMID: 17085958 [PubMed - indexed for MEDLINE]
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And finally gool old gingko biloba:
1: Acta Pharmacol Sin. 2004 Oct;25(10):1306-11.Links
Inhibitory effect of extracts of Ginkgo biloba leaves on VEGF-induced hyperpermeability of bovine coronary endothelial cells in vitro.Qiu Y, Rui YC, Li TJ, Zhang L, Yao PY.
Department of Pharmacology, School of Pharmacy, Second Medical Military University, Shanghai 200433, China.
AIM: To study whether extract of Ginkgo biloba (EGb) can protect against atherosclerosis. METHODS: Confluent monolayers of bovine coronary endothelial cells (BCECs), bovine coronary smooth muscle cells (BCSMCs), and cocultures of the two were incubated with medium containing VEGF and/or EGb, and flux of 125I-labeled oxidized low density lipoprotein (ox-LDL) across the monolayers was measured. RESULTS: Incubation with VEGF significantly increased the permeability of BCEC monolayers to 125I-ox-LDL in a time- and concentration-dependent manner, but had no effect on permeability of BCSMCs or endothelial cells-smooth muscle cells cocultures. EGb significantly inhibited the VEGF-induced hyperpermeability of BCECs. CONCLUSION: VEGF was important in the formation and development of atherosclerosis. The inhibition of VEGF-induced permeability by EGb suggests that extracts of Ginkgo biloba leaves may have important clinical applications in the treatment of cardiovascular diseases. Copyright 2004 Acta Pharmacologica Sinica
PMID: 15456532 [PubMed - indexed for MEDLINE
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and finally finally good old salvia:
1: J Nat Prod. 2007 Jul;70(7):1093-7. Epub 2007 Jun 21. Links
Abietane diterpenes from Salvia miltiorrhiza inhibit the activation of hypoxia-inducible factor-1.Dat NT, Jin X, Lee JH, Lee D, Hong YS, Lee K, Kim YH, Lee JJ.
Molecular Cancer Research Center, Korean Research Institute of Biosciences and Biotechnology, Daejeon 305-333, Korea.
The hypoxia-inducible factor-1 (HIF-1) has been known to be correlated to the adaptation and proliferation of tumor cells; therefore HIF-1 has become an important target in the development of anticancer drugs. A phytochemical study of the CHCl3-soluble fraction of Salvia miltiorrhiza, which strongly inhibited hypoxia-induced reporter gene expression, led to the isolation of 12 abietane-type diterpenes. Of these compounds, sibiriquinone A (1), sibiriquinone B (2), cryptotanshinone (3), and dihydrotanshinone I (4) potently inhibited hypoxia-induced luciferase expression with IC50 values of 0.34, 3.36, 1.58, and 2.05 microM on AGS cells, a human gastric cancer cell line, and 0.28, 3.18, 1.36, and 2.29 microM on Hep3B cells, a human hepatocarcinoma cell line, respectively. Consistently, 1 and 4 dose-dependently suppressed the HIF-1alpha accumulation and 1 inhibited mRNA expression of vascular endothelial growth factor (VEGF) under hypoxia. These results suggest that the anticancer activity of tanshinones is likely at least in part associated with their inhibition of HIF-1 accumulation.
PMID: 17583950 [PubMed - indexed for MEDLINE]
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oops. forgot rhubarb root:
1: Int J Cancer. 2006 Jun 1;118(11):2711-20. Links
Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation.Kwak HJ, Park MJ, Park CM, Moon SI, Yoo DH, Lee HC, Lee SH, Kim MS, Lee HW, Shin WS, Park IC, Rhee CH, Hong SI.
Laboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Emodin (1,3,8-trihydroxy-6-methylanthraquinone), an active component in the root and rhizome of Rheum palmatum, is a tyrosine kinase inhibitor with a number of biological activities, including antitumor effects. Here, we examine the effects of emodin on vascular endothelial growth factor (VEGF)-A-induced angiogenesis, both in vitro and in vivo. In vitro, emodin dose-dependently inhibits proliferation, migration into the denuded area, invasion through a layer of Matrigel and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated with VEGF-A. Emodin also inhibits basic fibroblast growth factor-induced proliferation and migration of HUVECs and VEGF-A-induced tube formation of human dermal microvascular endothelial cells. Specifically, emodin induces the cell cycle arrest of HUVECs in the G0/G1 phase by suppressing cyclin D1 and E expression and retinoblastoma protein phosphorylation, and suppresses Matrigel invasion by inhibiting the basal secretion of matrix metalloproteinase-2 and VEGF-A-stimulated urokinase plasminogen activator receptor expression. Additionally, emodin effectively inhibits phosphorylation of VEGF-A receptor-2 (KDR/Flk-1) and downstream effector molecules, including focal adhesion kinase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, Akt and endothelial nitric oxide synthase. In vivo, emodin strongly suppresses neovessel formation in the chorioallantoic membrane of chick and VEGF-A-induced angiogenesis of the Matrigel plug in mice. Our data collectively demonstrate that emodin effectively inhibits VEGF-A-induced angiogenesis in vitro and in vivo. Moreover, inhibition of phosphorylation of KDR/Flk-1 and downstream effector molecules is a possible underlying mechanism of the anti-angiogenic activity of emodin. Based on these data, we propose that an interaction of emodin with KDR/Flk-1 may be involved in the inhibitory function of emodin toward VEGF-A-induced angiogenesis in vitro and responsible for its potent anti-angiogenic in vivo.
PMID: 16388516 [PubMed - indexed for MEDLINE]
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and ganoderma lucidum:
1: Life Sci. 2006 Feb 23;78(13):1457-63. Epub 2005 Nov 2. Links
Ganoderma lucidum polysaccharides peptide inhibits the growth of vascular endothelial cell and the induction of VEGF in human lung cancer cell.Cao QZ, Lin ZB.
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100083, China.
Ganoderma lucidum Polysaccharide Peptide (Gl-PP) has shown some effects as anti-tumors in mice and potential anti-angiogenesis. In this study, we elucidated the possible mechanism of Gl-PP action on anti-angiogenesis of tumor. Our research indicated that the proliferation of HUVECs was inhibited by Gl-PP in a dose-dependent fashion, but not because of cytotoxicity. Flow cytometric studies revealed that Gl-PP treatment of HUVECs could induce cell apoptosis directly. Moreover, addition of Gl-PP also led to a reduction of Bcl-2 anti-apoptotic protein expression and an increase of Bax pro-apoptotic protein expression of HUVECs. Therefore, inducing cell apoptosis by Gl-PP might be the mechanism of inhibiting HUVEC proliferation. Human lung carcinoma cells PG when exposed to high dose of Gl-PP in hypoxia for 18 h resulted in a decrease in the secreted VEGF. Taken together, these findings support the hypothesis that the key attribute of the anti-angiogenic potential of Gl-PP is that it may directly inhibit vascular endothelial cell proliferation or indirectly decrease growth factor expression of tumor cells.
PMID: 16269156 [PubMed - indexed for MEDLINE]
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However I tried ganoderma lucidum in quite high dose during the summer and found my leg stiffer. BUT now that salvia is working so well perhaps it would improve matters. And the alpha lipoic is making my leg stiffer too. Mmm. Have reduced the alpha lipoic to 1.5g today.
Alas all of the vascular endothelial growth factor inhibitors listed above would be bad in pregnancy. So I won't be experimenting for a while. Could dysregulation at the VEGF level be why women suffer disproportionately? We need plenty of VEGF for healthy placental growth and we are hit in our child-bearing years.
Must eat rhubarb:
1: Zhongguo Zhong Yao Za Zhi. 2008 Mar;33(6):672-5.Links
[Protective mechanism on the vascular pathological process in diabetes mellitus rats by Rheum officeinale][Article in Chinese]
Tian FS, Li ZB, Wang YS, Su XH, Li WD, Wang XY.
Endocrinology Department, CangZhou Affiliated hospital of integrated TCM-WM, Hebei Medical University, Cangzhou 061001, China.
cztianfsh@sian.com
OBJECTIVE: To explore the protective mechanism of officeihale on the vascular pathological process in diabetes mellitus (DM) rats. METHOD: After the DM rat model was established, 24 DM rats were randomly divided into model group (12 DM rats) and Rheum officeinale group (12 DM rats). Rheum officeinale was orally given in 10 g kg(-1) per day, and the other two groups were given equal pure water. 8 weeks later, blood samples were collected to determine the level of nitric oxide (NO) and endothelin-1 (ET-1). Thoracic aortic rings was prepared to observe the inhibiting effect of Ach with different concentration on contraction caused by NE. Another part of aorta was made to observe the expression of ICAM-1 and VCAM-1 by method of SP immunohistochemistry staining, RESULT:
Rheum officeinale group obviously decreased the level of ET-1 and increased the NO compared with model group (P <0.05).
The expression of ICAM-1 and VCAM-1 could be obviously inhibited in Rheum officeinale group compared with model group. (P <0.05). CONCLUSION: Rheum officeinale could decrease the level of ET-1 with increased the NO in diabetes rats, and inhibit the expression of ICAM-1 and VCAM-1, which may be mechanisms of protecting the endothelium of vessel in diabetes rats.
PMID: 18590198 [PubMed - in process]
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