stilbenes and Hyperplasia

Intimal hyperplasia is the major therapeutic concern after percutaneous coronary intervention. The aim of this study is to investigate effects of 2,3,4',5-tetrahydroxystilbene-2-O-β-D glucoside (TSG) on intimal hyperplasia and the underling mechanisms through attenuating the expressions of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1, and through promoting re-endothelialization with vascular endothelial growth factor (VEGF).. Rats were operated with carotid artery balloon injury. The treatment groups were gavaged with 50 and 100 mg/kg/d of TSG. After 10 days of treatment, carotid artery pathological changes were evaluated by histology. Serum levels of SDF-1α, SCF, FKN and VEGF were detected by enzyme linked immunosorbent assay. The protein expressions of the receptors c-kit, CXCR4, CX3CR1, as well as CD34 and proliferating cell nuclear antigen (PCNA) were detected by immunochemistry.. TSG dose-dependently inhibited balloon injury-induced intimal hyperplasia, as evidenced by reducing neointima area (NIA), neointima area/media area (NIA/MA), neointima area/internal elastic area (NIA/IELA), and by decreasing the protein expression of PCNA. TSG reduced serum levels of SDF-1α, SCF and FKN, and it also decreased the expressions of the corresponding receptors c-kit, CXCR4, CX3CR1 in neointima. Importantly, the level of VEGF in peripheral blood and the expression of CD34 in vascular walls were increased to promote re-endothelialization.. This study clearly demonstrated that TSG was effective in inhibiting intimal hyperplasia, and this effect was mediated, at least in part, through the SCF/c-kit, SDF-1α/CXCR4 and FKN/CX3CR1 axes. Importantly, TSG could increase VEGF and CD34 to promote endothelial repair.

Topics: Angioplasty, Balloon; Animals; Carotid Artery Injuries; Carotid Artery, Common; Chemokine CX3CL1; Chemokine CXCL12; Glucosides; Hyperplasia; Male; Neointima; Random Allocation; Rats; Rats, Sprague-Dawley; Stem Cell Factor; Stilbenes; Vascular Endothelial Growth Factor A

Resveratrol has been reported to inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia following arterial injury; however, the underlying mechanisms remain unclear. The present study was designed to investigate the effects of resveratrol on angiotensin II (AngII)‑induced proliferation of A7r5 cells and explore the molecular mechanisms responsible for the observed effects. Resveratrol inhibited cell proliferation and migration, and decreased the AngII‑induced protein expression of α‑smooth muscle actin (α‑SMA), proliferating cell nuclear antigen (PCNA) and cyclin‑dependent kinase 4 (CDK4). Resveratrol inhibited AngII‑induced activation of intracellular Ca2+/calmodulin‑dependent protein kinase II (CaMKII) and histone deacetylases 4 (HDAC4), as well as blocking AngII‑induced cell cycle progression from the G0/G1 to S‑phase. In vivo, 4‑weeks of resveratrol treatment decreased the neointima area and the neointima/media area ratio in rats following carotid balloon injury. Resveratrol also inhibited the protein expression of total and phosphorylated CaMKII and HDAC4 in the injured arteries. In conclusion, the present study demonstrated that resveratrol attenuated AngII‑induced cell proliferation and neointimal hyperplasia by inhibiting the CaMKII‑HDAC4 signaling pathway. These findings suggest that resveratrol may potentially prevent arterial restenosis.

Topics: Angiotensin II; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Cycle; Cell Line; Histone Deacetylases; Hyperplasia; Male; Neointima; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes

Restenosis due to intimal hyperplasia is a major clinical problem that compromises the success of angioplasty and endovascular surgery. Resveratrol (RSV) has demonstrated a beneficial effect on restenosis from angioplasty. Unfortunately, the physicochemical characteristics of RSV reduce the practicality of its immediate clinical application. This work proposes an experimental model aiming to setup an intravessel, elutable, RSV-containing compound.. A 140 μg/mL RSV sterile injectable solution with a suitable viscosity for intravascular administration by drug-delivery catheter (RSV-c) was prepared. This solution was locally administered in the common iliac artery of adult male New Zealand White rabbits using a dedicated device (Genie; Acrostak, Geneva, Switzerland) after the induction of intimal hyperplasia by traumatic angioplasty. The RSV concentrations in the wall artery were determined, and the thickness of the harvested iliac arteries was measured over a 1-month period.. The Genie catheter was applied in rabbit vessels, and the local delivery resulted in an effective reduction in restenosis after plain angioplasty. Notably, RSV-c forced into the artery wall by balloon expansion might accumulate in the interstitial areas or within cells, avoiding the washout of solutions. Magnification micrographs showed intimal proliferation was significantly inhibited when RSV-c was applied. Moreover, no adverse events were documented in in vitro or in vivo studies.. RSV can be advantageously administered in the arterial walls by a drug-delivery catheter to reduce the risk of restenosis.

Topics: Angioplasty, Balloon; Animals; Cardiovascular Agents; Cell Proliferation; Cells, Cultured; Coated Materials, Biocompatible; Disease Models, Animal; Equipment Design; Humans; Hyperplasia; Iliac Artery; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Rabbits; Resveratrol; Stilbenes; Vascular Access Devices; Vascular System Injuries

The present study aimed to determine the protective effects of dietary supplementation with resveratrol (RSV) in an acute antigen-induced arthritis (AIA) model.. Rats were randomly divided into three groups: control, AIA and RSV-treated AIA group. RSV (12.5 mg/kg/day) was given orally for 8 weeks before induction of AIA and until the end of the experiment (48 h after intra-articular injection). The control and AIA animals were administered 100 μl of water. Results were evaluated by macroscopic observation, histopathology and immunohistochemistry for anti-PCNA, macrophages (CD68), T lymphocytes (CD3), monocyte chemoattractant protein-1 and 8-oxo-7,8-dihydro-2'-deoxyguanine (a marker of DNA damage). Cytokine-induced neutrophil chemoattractant-1 in serum and peroxidase activity in synovial tissue were measured using commercial kits.. At the end of the study, RSV significantly reduced knee swelling. Likewise, the histological score of synovial tissue also reduced significantly. The arthritis-protective effects were associated with a significant decrease in PCNA, CD68, CD3 and monocyte chemoattractant protein-1 staining, as well as a reduction in serum concentrations of cytokine-induced neutrophil chemoattractant-1. RSV treatment also decreased the level of the marker of DNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanine. Accordingly, peroxidase activity in the synovial tissue was up-regulated.. Dietary supplementation with RSV lowers the main pathological hallmarks of RA disease in an acute model of AIA. RSV may represent a promising strategy in controlling the severity of RA.

Topics: Animals; Antioxidants; Arthritis, Experimental; Cell Proliferation; Cytokines; DNA Damage; Dose-Response Relationship, Drug; Female; Hyperplasia; Immunity, Cellular; Peroxidase; Random Allocation; Rats, Inbred Lew; Resveratrol; Stilbenes; Synovial Membrane

We assessed the effect of resveratrol on intimal hyperplasia and endothelial proliferation after its use for carotid artery anastomosis in rabbits.. Fourteen New Zealand-type male rabbits, weighing a mean of 2-3 kg were selected randomly. Their right carotid arteries were transected and anastomosed side by side using 8/0 polypropylene. The rabbits were divided into two groups with seven in each group. While the rabbits in the first group were accepted as the Control group, the rabbits in the second group were given resveratrol (1 mg/kg/day) for 14 days intravenously. At the end of the 28th day, all the carotid artery segments that were transected and anastomosed and the left carotid arteries that did not undergo surgery were removed and evaluated histologically.. The results of histological evaluation were as follows: lumen diameter (P <0.001) and lumen area (P <0.05) of the Resveratrol group were larger than those of the Control group, intimal thickness (P <0.05) and media thickness of the Resveratrol group (P = 0.04) were thinner than those of the Control group, and intima/media ratio of the Control group was found to be greater than that of the Resveratrol group (P = 0.002).. Resveratrol can prevent intimal hyperplasia and endothelial proliferation following surgical anastomosis.

Topics: Anastomosis, Surgical; Animals; Carotid Arteries; Carotid Intima-Media Thickness; Cell Proliferation; Endothelial Cells; Hyperplasia; Male; Models, Animal; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Rabbits; Resveratrol; Stilbenes; Time Factors

Phenotypic switching of vascular smooth muscle cells (VSMCs) plays an initial role in neointimal hyperplasia, the main cause of many occlusive vascular diseases. The aim of this study was to measure the effects of resveratrol (RSV) on the phenotypic transformation of VSMCs and to investigate its mechanism of action.. Cultured VSMCs isolated from rat thoracic aorta were prepared with serum starvation for 72 hours followed by RSV treatment (50-200 μmol/L) and 10% serum stimulation. Male Sprague-Dawley rats, subjected to carotid arteries injury from a balloon catheter, were exposed to intraperitoneal injection of RSV (1 mg/kg) or saline and were killed after 7 or 28 days.. Compared with cells in the serum-induced group, VSMCs in the RSV or N-[N-(3, 5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) treatment group exhibited significant decreases of proliferation and migration. The total and cytoplasmic Notch-1 levels were declined by RSV, accompanied by a significant increase in smooth muscle α-actin and smooth muscle myosin heavy chain protein. The expression of Notch-1, Jagged-1, Hey-1, and Hey-2 mRNA in balloon-injured arteries at 7 days was decreased by RSV treatment. Arteries from RSV-treated rats showed less neointimal hyperplasia, lower collagen content, and a lower rate of cells positive for proliferating cell nuclear antigen 28 days after injury, compared with saline controls.. The results indicate that RSV can attenuate phenotypic switching of VSMCs after arterial injury through inhibition of the Notch pathway.

Topics: Animals; Antioxidants; Aorta, Thoracic; Carotid Arteries; Carotid Artery Injuries; Cells, Cultured; Disease Models, Animal; Hyperplasia; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Rats; Rats, Sprague-Dawley; Receptor, Notch1; Resveratrol; Stilbenes; Time Factors

Epigallocatechin-3-gallate (EGCG), a catechin gallate ester, is the major component of green tea and has been demonstrated to inhibit tumor growth as well as inhibit smooth muscle cell migration. We evaluated the effect of the phytochemicals resveratrol, allicin, sulforaphane (SFN), and EGCG on intimal hyperplasia in the carotid artery injury model.. Intimal hyperplasia was induced in carotid arteries of adult Sprague-Dawley rats with a wire injury. Experimental animals received intraperitoneal injections of one of the four phytochemicals daily beginning 1 day prior to surgery and continued for up to 4 weeks. Control animals were administered saline. Carotid specimens were harvested at 2 weeks and subjected to quantitative image analysis. In addition, EGCG specimens were analyzed for cell proliferation, immunohistochemistry, and Western blot analysis.. Quantitative image analysis showed significant phytochemical suppression of intimal hyperplasia at 2 and 4 weeks postoperatively with EGCG (62% decrease in intimal area). Significant decreases were also noted at 2 weeks for SFN (56%) and resveratrol (44%), whereas the decrease with allicin (24%) was not significant. Quantification of intimal hyperplasia by intima:media ratio showed similar results. Cell proliferation assay of specimens demonstrated suppression by EGCG. Immunohistochemical staining of EGCG-treated specimens showed extracellular signal-regulated kinase (ERK) suppression but not of the c-jun N-terminal kinase or p38 pathways. Western blot analysis confirmed reduced ERK activation in arteries treated with EGCG.. Intraperitoneal injection of the phytochemicals EGCG, SFN, resveratrol, and allicin have suppressive effects on the development of intimal hyperplasia in the carotid artery injury model, with maximal effect due to EGCG. The mechanism of EGCG action may be due to inhibition of ERK activation. EGCG may affect a common pathway underlying either neoplastic cellular growth or vascular smooth muscle cellular proliferation.

Topics: Animals; Cardiovascular Agents; Carotid Artery Injuries; Carotid Artery, Common; Carotid Intima-Media Thickness; Catechin; Cell Proliferation; Disease Models, Animal; Disulfides; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hyperplasia; Injections, Intraperitoneal; Isothiocyanates; Male; Neointima; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Sulfinic Acids; Sulfoxides; Time Factors

2,3,4',5-tetrahydroxystilbene-2-0-β-D glucoside (TSG) has been recognized to suppress the proliferation of vascular smooth muscle cells (VSMCs). The aim of the present study was to determine whether TSG inhibits neointimal hyperplasia in a rat carotid arterial balloon injury model. Balloon injury was induced in the left common carotid artery of rats. TSG (30, 60, 120 mg/kg/day) was treated from 3 days prior to, until 14 days after the induction of balloon injury. The ratio of intima-to-media was significantly reduced in the TSG-treated rats at 14 days after the induction of injury, which was associated with reduced expressions of proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA) and platelet-derived growth factor-BB (PDGF-BB), as markers of VSMCs proliferation and migration. Additionally, TSG significantly inhibited PDGF-BB induced cell migration in cultured VSMCs. Furthermore, we explored the underlying mechanisms for such effects of TSG. The result showed that TSG markedly reduced balloon injury-induced AKT, extracellular signal-regulated kinase (ERK1/2) and nuclear factor kappaB (NF-κB) activation as well as mRNA expressions of c-myc, c-fos and c-jun, which is important signal pathway for VSMCs proliferation. And in both vivo and vitro model, TSG markedly regulated matrix metalloproteinase-2, 9 expressions and collagen I, III expressions, which are key factors in extracellular matrix for VSMCs migration. These results suggest that the anti-proliferative and anti-migrative effects of TSG on VSMCs could help to explain the beneficial effects of TSG on neointima hyperplasia induced by balloon injury.

Topics: Animals; Becaplermin; Carotid Arteries; Carotid Artery Injuries; Catheters; Cell Movement; Extracellular Matrix; Gene Expression Regulation; Glucosides; Hyperplasia; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Neointima; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Signal Transduction; Stilbenes

Late-term thrombosis associated with drug-eluting stents may be due to the non-selective actions of antimitogenic drugs on endothelial cells, leading to delayed vascular healing after stenting angioplasty. Currently, there is a need for stent-based therapies that can both attenuate neointimal hyperplasia and promote re-endothelialization. The aim of this study was to compare the effects of a resveratrol (R)- and quercetin (Q)-eluting stent with that of a bare metal stent (BMS) on neointimal hyperplasia and re-endothelialization in a rat model of arterial angioplasty and stenting. Miniature stents (2.5×1.25mm) were sprayed with nanocomposite coatings containing two concentrations of R:Q (50:25μg/cm(2) (RQ1) or 150:75μg/cm(2) (RQ2)). The stents were deployed into the common carotid artery of rats and their impact on vascular remodeling was compared to that of BMS. Luminal stenosis in arteries stented with RQ2-eluting stents was reduced by 64.6% (p<0.05) compared to arteries stented with BMS. Accompanying this effect was a 59.8% reduction in macrophage infiltration (p<0.05). There were no differences found between RQ1 and BMS. Finally, the RQ2-coated stent accelerated re-endothelialization by 50% compared with BMS (p<0.05). Thus, compared with BMS, local delivery of R and Q from a stent platform significantly reduced in-stent stenosis, while promoting re-endothelialization. These data suggest that R and Q may be favorable candidates for novel stent coatings, potentially reducing the risk of late thrombosis associated with drug-eluting stents.

Topics: Angioplasty; Animals; Antimitotic Agents; Cell Proliferation; Constriction, Pathologic; Drug-Eluting Stents; Endothelium, Vascular; Female; Hyperplasia; Male; Nanocomposites; Neointima; Quercetin; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Restenosis is a critical complication of angioplasty and stenting. Restenosis is multifactorial, involving endothelial injury, inflammation, platelet activation, and vascular smooth muscle cell (VSMC) proliferation. Thus, dietary strategies to prevent restenosis likely require the use of more than one agent. Resveratrol (R) and quercetin (Q) are polyphenols that are known to exhibit vascular protective effects. We tested whether R and Q administered in the diet interact to inhibit vessel stenosis in mice with a carotid injury. B6.129 mice were administered a high-fat diet containing 21% fat and 0.2% cholesterol along with R (25 mg/kg), Q (10 mg/kg), or R + Q for 2 wk. A carotid injury was induced and the mice were again administered the enriched diet for 2 wk. Compared with the controls, R significantly decreased stenosis, assessed as an intima:media ratio, by 76%. Although Q treatment alone exhibited no effect, it potentiated the effect of R in that treatment with R + Q significantly decreased the intima:media ratio by 94%. Moreover, this effect was greater than that of R treatment alone (P < 0.05). Although treatments with R, Q, and R + Q significantly affected platelet activation and endothelial function, the responses observed for R + Q were less than additive. Specifically, the effects of R + Q were less than the sum of effects for treatments with R and Q alone. In contrast, treatment with R + Q exhibited more-than-additive effects on inflammatory markers and significant interactions between R and Q were observed. The presence of synergy between R and Q was thus tested in cultures of VSMC and macrophages. Isobolographic analysis revealed that 2:1 molar ratios of R:Q exhibited synergistic inhibition of VSMC proliferation and macrophage chemotaxis. In conclusion, in combination, R and Q can interact to reduce the extent of restenosis, perhaps due to their synergistic inhibition of VSMC proliferation and inflammation.

Topics: Animals; Antioxidants; Carotid Artery Injuries; Cell Proliferation; Chemotaxis; Drug Interactions; Endothelial Cells; Endothelium, Vascular; Female; Hyperplasia; Inflammation; Mice; Monocytes; Neointima; Quercetin; Resveratrol; Stilbenes; Thromboxane B2

Philadelphia chromosome-negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are disorders characterized by abnormal hematopoiesis. Among these myeloproliferative neoplasms, myelofibrosis has the most unfavorable prognosis. Furthermore, currently available therapies for myelofibrosis have little to no efficacy in the bone marrow and hence, are palliative. We recently developed a Janus kinase 2 (Jak2) small molecule inhibitor called G6 and found that it exhibits marked efficacy in a xenograft model of Jak2-V617F-mediated hyperplasia and a transgenic mouse model of Jak2-V617F-mediated polycythemia vera/essential thrombocytosis. However, its efficacy in Jak2-mediated myelofibrosis has not previously been examined. Here, we hypothesized that G6 would be efficacious in Jak2-V617F-mediated myelofibrosis. To test this, mice expressing the human Jak2-V617F cDNA under the control of the vav promoter were administered G6 or vehicle control solution, and efficacy was determined by measuring parameters within the peripheral blood, liver, spleen, and bone marrow. We found that G6 significantly reduced extramedullary hematopoiesis in the liver and splenomegaly. In the bone marrow, G6 significantly reduced pathogenic Jak/STAT signaling by 53%, megakaryocytic hyperplasia by 70%, and the Jak2 mutant burden by 68%. Furthermore, G6 significantly improved the myeloid to erythroid ratio and significantly reversed the myelofibrosis. Collectively, these results indicate that G6 is efficacious in Jak2-V617F-mediated myelofibrosis, and given its bone marrow efficacy, it may alter the natural history of this disease.

Topics: Amino Acid Substitution; Animals; Bone Marrow; Disease Models, Animal; Hematopoiesis, Extramedullary; Humans; Hyperplasia; Janus Kinase 2; Megakaryocytes; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myeloid Cells; Phosphorylation; Primary Myelofibrosis; Protein Kinase Inhibitors; Reticulin; Small Molecule Libraries; Spleen; Splenomegaly; STAT5 Transcription Factor; Stilbenes

Neointima, defined as abnormal growth of the intimal layer of blood vessels, is believed to be a critical event in the development of vascular occlusive disease. Although resveratrol's inhibitory effects on proliferation and migration of vascular smooth muscle cells has been reported, its activity on neointimal formation is still unclear. Oral administration of trans-resveratrol significantly suppressed intimal hyperplasia in a wire-injured femoral artery mouse model. In cultured vascular smooth muscle cells, trans-resveratrol inhibited platelet-derived growth factor-stimulated DNA synthesis and cell proliferation with down-regulation of cyclin D and pRB. Moreover, platelet-derived growth factor-induced production of reactive oxygen species was inhibited by trans-resveratrol and the compound induced heme oxygenase-1 (HO-1). The anti-proliferative activity of trans-resveratrol was reversed by an HO-1 inhibitor, ZnPPIX. Subcellular fractionation and reporter gene analyses revealed that trans-resveratrol increased the level of nuclear Nrf2 and antioxidant response element reporter activity, and that these were essential for the induction of HO-1. Trans-resveratrol also enhanced the activities of phosphatidyl inositol 3-kinase and extracellular signal regulated kinase, and phosphatidyl inositol 3-kinase was required for Nrf2/antioxidant response element-dependent HO-1 induction. These data have significant implications for the elucidation of the pharmacological mechanism by which trans-resveratrol prevents vascular occlusive diseases.

Topics: Animals; Aorta, Thoracic; Arterial Occlusive Diseases; Cell Line; Cell Nucleus; Cell Proliferation; Cells, Cultured; Cyclin D; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Femoral Artery; Heme Oxygenase-1; Hyperplasia; Membrane Proteins; Mice; Muscle, Smooth, Vascular; Neointima; NF-E2-Related Factor 2; Phosphoinositide-3 Kinase Inhibitors; Protein Transport; Rats; Reactive Oxygen Species; Resveratrol; Retinoblastoma Protein; Stilbenes

Hepatocellular carcinoma (HCC), one of the most frequent and deadliest cancers, has been increasing considerably in the United States. In the absence of a proven effective therapy for HCC, novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality of HCC. Recently, we have reported that resveratrol, a compound present in grapes and red wine, significantly prevents diethylnitrosamine (DENA)-induced liver tumorigenesis in rats, although the mechanism of action is not completely understood. In the present study, we have examined the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by investigating the effects of resveratrol on oxidative damage and inflammatory markers during DENA-initiated rat liver carcinogenesis. There was a significant increase in hepatic lipid peroxidation and protein oxidation in carcinogen control animals compared with their normal counterparts at the end of the study (20 weeks). Elevated expressions of inducible nitric oxide synthase and 3-nitrotyrosine were noticed in the livers of the same animals. Dietary resveratrol (50-300 mg/kg) administered throughout the study reversed all the aforementioned markers in a dose-responsive fashion in rats challenged with DENA. Resveratrol also elevated the protein and mRNA expression of hepatic nuclear factor E2-related factor 2 (Nrf2). Results of the present investigation provide evidence that attenuation of oxidative stress and suppression of inflammatory response mediated by Nrf2 could be implicated, at least in part, in the chemopreventive effects of this dietary agent against chemically induced hepatic tumorigenesis in rats. The outcome of this study may benefit the development of resveratrol in the prevention and intervention of human HCC.

Topics: Animals; Antioxidants; Carcinogens; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Induction; Female; Hyperplasia; Inflammation; Lipid Peroxidation; Liver; Liver Neoplasms, Experimental; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Oxidative Stress; Phenobarbital; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Stilbenes; Tyrosine

The ability of resveratrol to inhibit vascular intimal thickening was tested in an experimental model in which endothelial denudation was performed in the normal rabbit iliac artery. Resveratrol (2 approximately 4mg/ kg/d) was administered intragastrically for 5 weeks beginning 1 week before denudation. At the higher concentration of resveratrol, the intimal hyperplasia of injured vascular wall was effectively inhibited; the intimal proliferation index also was significantly less than that in the untreated control group (0.28 +/- 0.07 vs 0.41 +/- 0.13, respectively, p<0.01); the relative luminal area increased from 0.38 +/- 0.06 in the untreated control group to 0.53 +/- 0.10 in the resveratrol treatment group (p < 0.001); and the count of smooth muscle cells in the thickened intima was statistically significantly reduced in the high dose resveratrol treatment group than that in the untreated group (1,115 +/- 510 vs 1,796 +/- 963, respectively, p < 0.05). Resveratrol added to the culture media of cultured rabbit vascular smooth muscle cells inhibited DNA synthesis in a dose-dependent manner. These results showing that resveratrol is capable of inhibiting intimal hyperplasia of injured artery raise the possibility that this polyphenol might have clinical potential in prevention and treatment of restenosis after angioplasty.

Topics: Animals; Antioxidants; Cattle; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Graft Occlusion, Vascular; Hyperplasia; Iliac Artery; Male; Muscle, Smooth, Vascular; Rabbits; Resveratrol; Stilbenes; Tunica Intima

After repeated administration of trans-4-acetylaminostilbene to rats, DNA-bound metabolites accumulate to the greatest extent in liver and kidney, which are considered to be nontarget tissues for this carcinogen. To test whether the persistent DNA adducts represent procarcinogenic lesions, an initiation-promotion experiment was carried out using trans-4-acetylaminostilbene as an initiator and phenobarbital, DDT and diethylstilbestrol as promoters. In addition, partial hepatectomy was performed in some groups. Partial hepatectomy alone or in combination with promoters led to the formation of preneoplastic enzyme deficient foci, hyperplastic nodules and hepatoma in great yields. In addition, mammary tumors were observed with diethylstilbestrol promotion. The results support our proposal that aminostilbene derivatives produce procarcinogenic DNA-lesions in many, if not all, tissues and that secondary factors determine when and where tumors arise.

Topics: Adenoma, Bile Duct; Animals; Bile Duct Neoplasms; Body Weight; Carcinogens; DNA; Female; Hyperplasia; Liver; Liver Neoplasms, Experimental; Liver Regeneration; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Stilbenes

Topics: Abnormalities, Drug-Induced; Animals; Cervix Uteri; Diethylstilbestrol; Estradiol; Fallopian Tubes; Female; Genital Neoplasms, Female; Genitalia, Female; Hyperplasia; Metaplasia; Mice; Ovary; Pregnancy; Stilbenes; Uterus; Vagina

Topics: Diethylstilbestrol; DNA Nucleotidyltransferases; Estradiol; Humans; Hyperplasia; Male; Prostatic Neoplasms; Stilbenes

Topics: 17-Ketosteroids; Adenocarcinoma; Atrophy; Chorionic Gonadotropin; Clomiphene; Diagnosis; Drug Therapy; Endometriosis; Endometrium; Female; Follicle Stimulating Hormone; Genital Diseases, Female; Gonadotropins; Humans; Hyperplasia; Infertility; Infertility, Female; Ovulation; Pathology; Polycystic Ovary Syndrome; Stilbenes; Toxicology; Urine; Uterine Neoplasms

Topics: Animals; Azo Compounds; Carcinogens; Coloring Agents; Cricetinae; Dogs; Furans; Hydrocarbons; Hyperplasia; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Rats; Research; Stilbenes; Urinary Bladder Diseases; Urinary Bladder Neoplasms