tranilast and Body-Weight

Abnormal expression of stromal cells and extracellular matrix in tumor stroma creates a tight barrier, leading to insufficient extravasation and penetration of therapeutic agents. Cancer-associated fibroblasts (CAFs) take on pivotal roles encouraging tumor progression.. To surmount the refractoriness of stroma, we constructed a multi-targeting combined scenario of anti-CAFs agent tranilast and antitumor agent docetaxel micelles (DTX-Ms). Tranilast cut down crosstalk between tumor cells and stromal cells, ameliorated the tumor microenvironment, and enhanced the antiproliferation efficacy of DTX-Ms on cancer cells.. Diverse experiments demonstrated that tranilast enhanced DTX-Ms' antitumor effect in a two-stage pattern by CAFs ablation, tumor cell migration blocking, and metastasis inhibition. Along with activated CAFs decreasing in vivo, the two-stage therapy succeeded in reducing interstitial fluid pressure, normalizing microvessels, improving micelles penetration and retention, and inhibiting tumor growth and metastasis. Interestingly, tranilast alone failed to inhibit tumor growth in vivo, and it could only be used as an adjuvant medicine together with an antitumor agent.. Our proposed two-stage therapy offers a promising strategy to enhance antitumor effects by breaking down CAFs barrier and increasing micellar delivery efficiency.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Movement; Cell Proliferation; Docetaxel; Extracellular Fluid; Female; Humans; Mice; Mice, Inbred BALB C; Micelles; Microvessels; Neoplasm Metastasis; Neoplasms; Organ Specificity; ortho-Aminobenzoates; Spheroids, Cellular; Taxoids; Tissue Distribution; Tumor Microenvironment

To test the hypothesis that stimulation of chymase secretion may contribute to plaque vulnerability and inhibition of chymase activity may enhance plaque stability.. Sixty eight-week-old male Syrian golden hamsters were randomly divided into normal control group, high-cholesterol (HC) treated group, HC+ovalbumin treated group and HC+tranilast treated group. The normal control group received a normal diet while the other three intervention groups received a high-cholesterol diet for 15 weeks. Hamsters in the HC+ovalbumin treated group underwent transcatheter pharmacological triggering at the end of week 15 after antigen sensitization and those in the HC+tranilast treated group were given tranilast intragastrically for 3 weeks before euthanasia. Serological, ultrasonographic, pathologic, immunohistochemical, and gene expression studies were performed in all animals. The total number of mast cells, proportion of degranulated mast cells and the number of extracellular granules in plaques, the apoptosis rate of vascular smooth cells, the local activities of chymase, the concentration of Ang II and the expression levels of inflammatory markers as well as plaque vulnerability index all increased significantly in HC+ovalbumin treated group, but remarkably decreased in HC+tranilast treated group, in comparison with the HC treated group. These results suggest that stimulation of chymase secretion contributes to plaque vulnerability while inhibition of chymase activity enhances plaque stability. We conclude that chymase activity provides a promising therapeutic target in the stabilization of atherosclerotic plaques.

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aorta; Apoptosis; Atherosclerosis; Body Weight; Cell Degranulation; Cholesterol; Chymases; Cricetinae; Disease Models, Animal; Disease Progression; Immunohistochemistry; Inflammation; Inflammation Mediators; Lipids; Male; Mast Cells; Mesocricetus; Microscopy, Electron, Transmission; ortho-Aminobenzoates; Ovalbumin; Peptidyl-Dipeptidase A; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Rupture; Time Factors; Ultrasonography, Doppler, Duplex

The present study was performed to investigate the effects of the antiallergic drug tranilast on the development of diabetic nephropathy in streptozotocin (50 mg/kg)-induced diabetic spontaneously hypertensive rats (SHR). Diabetic SHR were given standard chow or chow containing tranilast at a dose of 1400 mg/kg for 24 weeks. The effects of tranilast on urinary albumin excretion, mesangial expansion, expression of transforming growth factor-beta (TGF-beta) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-beta and 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion were assessed. Tranilast did not affect the blood glucose concentration or blood pressure in diabetic SHR. Urinary albumin excretion rate and creatinine clearance were markedly increased in diabetic SHR. Tranilast treatment decreased albuminuria and hyperfiltration. Tranilast inhibited the diabetes-induced expansion of mesangial and tuft areas, as well as the increase in urinary TGF-beta and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-beta as determined immunohistochemically. The levels of TGF-beta and type I collagen mRNA expression were increased in the renal cortex in untreated diabetic SHR at 24 weeks, as determined by real-time quantitative polymerase chain reaction. Tranilast treatment inhibited the up-regulation of TGF-beta and type I collagen mRNA expression by 65 and 36%, respectively, in diabetic SHR. In conclusion, tranilast decreased albuminuria by suppressing glomerular hyperfiltration, mesangial expansion, and loss of the charge barrier via regulation of extracellular matrix gene expression and oxidative stress. Tranilast may be clinically useful in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Collagen Type I; Diabetic Nephropathies; Disease Progression; Extracellular Matrix Proteins; Filtration; Gene Expression Regulation; Glomerular Mesangium; Hypertension, Renal; Immunohistochemistry; Kidney; Male; Nephrosclerosis; ortho-Aminobenzoates; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta

In order to study the association between myocardial fibrosis and inflammatory cell infiltration in the hypertensive heart, we investigated whether N(3,4-dimethoxycinnamoyl) anthranilic acid (tranilast), an anti-inflammatory drug, would suppress myocardial fibrosis via inhibition of inflammatory cell infiltration in deoxycorticosterone-acetate (DOCA) hypertensive rats.. Sprague-Dawley rats treated with DOCA combined with the addition of 1% NaCl and 0.2% KCl in the drinking water after left nephrectomy were given tranilast (100 mg/kg per day, n = 15) or vehicle (n = 15) for up to 4 weeks. Systolic blood pressure (SBP), amount of myocardial interstitial fibrosis, perivascular fibrosis and type I and III collagen, and mRNA expression of procollagen I (PI) and procollagen III (PIII), transforming growth factor (TGF)-beta1, type-1 plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were determined.. SBP was increased significantly 2 weeks after treatment with DOCA and salt. Myocardial interstitial fibrosis, perivascular fibrosis and collagen accumulation increased significantly 4 weeks after the treatment. Two weeks after the treatment with DOCA and salt, mRNA expression of PI and PIII, TGF-beta1, PAI-1, MCP-1 and IL-6 increased significantly. Although the SBP was similar in animals treated with tranilast or vehicle, monocyte/macrophage infiltration was suppressed, mRNA expression of TGF-beta1, PAI-1, MCP-1, IL-6, PI and PIII was attenuated, and myocardial fibrosis and collagen accumulation were suppressed in hypertensive animals receiving tranilast.. Myocardial fibrosis seen in DOCA/salt hypertensive rats might be associated with the inflammation/wound healing response. Tranilast suppresses both infiltration of monocytes/macrophages and myocardial fibrosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Cardiomegaly; Chemokine CCL2; Collagen Type I; Collagen Type III; Desoxycorticosterone; Fibrosis; Hypertension; Interleukin-6; Macrophages; Male; Monocytes; Myocardium; Nephrectomy; Organ Size; ortho-Aminobenzoates; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

Development of a new therapeutic approach to improve the prognosis of high grade invasion of oral squamous cell carcinoma is needed. To elucidate the effect of a fibroblast inhibitor (tranilast), we investigated the proliferation and metastasis of oral squamous cell carcinoma in a mouse model. The effect of tranilast on tumour growth, lymph node metastases, microvessel density, and the proliferating cell nuclear antigen (PCNA) labelling index of oral squamous cell carcinoma implanted into the tongue of nude mice was evaluated. Tumour growth and the incidence of cervical lymph node metastases were significantly suppressed by the administration of tranilast. The amount of fibrous tissue, the microvessel density, and the PCNA labelling index of tumour were also significantly reduced. Administration of a fibroblast inhibitor may well be clinically effective for the treatment of oral squamous cell carcinoma.

Topics: Animals; Antineoplastic Agents; Body Weight; Carcinoma, Squamous Cell; Cell Division; Female; Fibroblasts; Humans; Lymphatic Metastasis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Mouth Neoplasms; Neoplasm Transplantation; Neovascularization, Pathologic; ortho-Aminobenzoates; Tumor Cells, Cultured

We examined the inhibitory effects of traditional Chinese formulations (TCFs: Kampo formulation in Japanese) on intimal thickening of the carotid artery injured by balloon endothelial denudation in rats. Among the eight TCFs examined oren-gedoku-to (huanglian-jiedu-tang in Chinese), choto-san (diao-teng-san), saiko-ka-ryukotsu-borei-to (chaihujia-longgu-muli-tang) and dai-joki-to (da-cheng-qi-tang) significantly inhibited the intimal thickening 7 days after denudation. These four TCFs also inhibited proliferation of vascular smooth muscle cells (VSMC), which may play a central role in the development of restenosis after balloon endothelial denudation. The present results suggest that further evaluation of these four TCFs as inhibitors of VSMC proliferation to prevent arteriosclerosis is warranted.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Carotid Artery Injuries; Carotid Stenosis; Catheterization; Cell Division; Drugs, Chinese Herbal; Endothelium, Vascular; Indicators and Reagents; Luminol; Male; Muscle, Smooth, Vascular; ortho-Aminobenzoates; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar

We report here that the traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang (CLM), significantly inhibited the increase in intimal thickening in rat carotid artery injured by balloon endothelial denudation, which mimics many aspects of restenosis after percutaneous coronary intervention (PCI) in humans. CLM, Saiko-ka-Ryukotsu-Borei-to in Japanese, is commonly prescribed for symptoms accompanying hypertension and atherosclerosis in Japanese Kampo medical care. CLM administered orally 1 week before and 1, 4 and 8 weeks after balloon injury inhibited the increase in intimal area, intimal/medial ratio and stenosis ratio. To our knowledge, this is the first report demonstrating inhibitory effects of a traditional Chinese formulation on intimal thickening of carotid artery after balloon injury. It is worth noting that CLM maintained its inhibitory effect up to 8 weeks after balloon injury. The reduction in intimal thickening by CLM could have resulted from inhibition of intimal smooth muscle cell proliferation, which was assessed by immuno-histochemical analysis using monoclonal antibody against proliferating cell nuclear antigen. Therefore, CLM may be a favourable candidate for prevention of restenosis after PCI. Moreover CLM may have a therapeutic value in the prevention of atherosclerosis, because restenosis after PCI is considered to be an accelerated atherosclerosis.

Topics: Angioplasty, Balloon, Coronary; Animals; Body Weight; Carotid Artery Injuries; Carotid Stenosis; Cell Division; Drugs, Chinese Herbal; Eating; Endothelium, Vascular; Humans; Hyperplasia; Immunohistochemistry; Male; Medicine, Chinese Traditional; Medicine, Kampo; Molecular Structure; Muscle, Smooth, Vascular; ortho-Aminobenzoates; Platelet Aggregation Inhibitors; Postoperative Complications; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Tunica Intima

Cardiac allograft vasculopathy is a major complication after cardiac transplantation, often limiting long-term recipient survival. N-(3,4-Dimethoxycinnamoyl)anthranilic acid (tranilast) inhibits cyclin-dependent kinase activity through p21(Waf1/Cip1) induction and arrests vascular smooth muscle cell proliferation in vitro. We tested a hypothesis that tranilast inhibits the vasculopathy characterized by diffuse intimal thickening in a murine heart transplantation model. Hearts from DBA/2 mice were heterotopically transplanted into B10.D2 mice as allografts. Oral administration of tranilast started 3 days before transplantation at doses of 550 or 1040 mg/kg per day until the animals were killed. Cardiac allograft vasculopathy was defined as luminal stenosis caused by neointimal formation. The percentage of luminal stenosis and cardiac rejection were analyzed 14 and 28 days after transplantation. Tranilast administration was associated with a marked reduction in luminal occlusion but with no significant effect on cardiac rejection. Immunohistochemical study of the tranilast-treated graft coronary arteries revealed enhancement of p21(Waf1/Cip1) and decreased expression of proliferating cell nuclear antigen in the neointima. The significant reduction in allograft vasculopathy concomitant with the enhancement of p21(Waf1/Cip1) indicates that tranilast has an antiproliferative effect that could be applicable to clinical treatment of cardiac allograft vasculopathy.

Topics: Animals; Apoptosis; Body Weight; Coronary Artery Disease; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Graft Survival; Heart Transplantation; Immunohistochemistry; Kinetics; Male; Mice; Mice, Inbred DBA; ortho-Aminobenzoates; Proliferating Cell Nuclear Antigen; Transplantation, Homologous; Tumor Suppressor Protein p53

Inflammatory and immunological responses of vascular cells have been shown to play a significant role in the progression of atheromatous formation. Tranilast [N-(3,4-dimethoxycinnamoyl) anthranillic acid] inhibits release of cytokines and chemical mediators from various cells, including macrophages, leading to suppression of inflammatory and immunological responses. This study tested whether tranilast may suppress atheromatous formation in Watanabe heritable hyperlipidemic (WHHL) rabbits.. WHHL rabbits (2 months old) were given either 300 mg x kg-1 x d-1 of tranilast (Tranilast, n=12) or vehicle (Control, n=13) PO for 6 months. Tranilast treatment was found to suppress the aortic area covered with plaque. Immunohistochemical analysis showed that there was no difference in the percentage of the RAM11-positive macrophage area and the frequency of CD5-positive cells (T cells) in intimal plaques between Tranilast and Control. Major histocompatibility complex (MHC) class II expression in macrophages and interleukin-2 (IL-2) receptor expression in T cells, as markers of the immunological activation in these cells, was suppressed in atheromatous plaque by tranilast treatment. Flow cytometry analysis of isolated human and rabbit peripheral blood mononuclear cells showed that an increase in expression both of MHC class II antigen on monocytes by incubation with interferon-gamma and of IL-2 receptor on T cells by IL-2 was suppressed by the combined incubation with tranilast.. The results indicate that tranilast suppresses atherosclerotic development partly through direct inhibition of immunological activation of monocytes/macrophages and T cells in the atheromatous plaque.

Topics: Administration, Oral; Animals; Anti-Allergic Agents; Antigens, Surface; Aorta; Arteriosclerosis; Body Weight; Calcium; Hemodynamics; Humans; Hyperlipidemias; Intracellular Membranes; Lipid Metabolism; Lipids; Lipoproteins, LDL; Monocytes; N-Formylmethionine Leucyl-Phenylalanine; ortho-Aminobenzoates; Oxidation-Reduction; Rabbits

Tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, a widely used antiallergy drug in Japan, has been shown to inhibit transforming growth factor-beta1 release from fibroblasts and reduce collagen synthesis in keloid cells. In the present study, we have investigated the effect of this drug on cardiac hypertrophy in spontaneously hypertensive rats (SHR), with a focus on the cardiac collagen matrix, which is associated with myocardial stiffness. Twenty-four-week-old SHRs and Wistar Kyoto rats (WKYs) were administered tranilast (300 mg/kg) orally once a day for 4 weeks. This treatment significantly suppressed increases in left ventricular collagen concentration (P < 0.05) and the left ventricular weight/body weights ratios (P < 0.05) in SHRs, and tranilast was ineffective on collagen concentration and ventricular weight/body weights ratios in WKYs. Tranilast did not affect systolic or diastolic blood pressure, end-diastolic left ventricular pressure and heart rate in both SHRs and WKYs, and the agent did not change positive dp/dt or cardiac output in SHRs. The pressure-volume relationship curve was shifted to the left by the drug; the slope (k) of the logarithm of the pressure-volume relationship curve was significantly increased (P < 0.05) in SHRs. It is concluded that the suppression of increases in cardiac collagen and left ventricular mass by tranilast results in a corresponding prevention of cardiac stiffness as studied in the SHR.

Topics: Animals; Anti-Allergic Agents; Blood Pressure; Body Weight; Cardiac Output; Cardiomegaly; Collagen; Heart; Heart Rate; Heart Ventricles; Hemodynamics; Hydroxyproline; Male; Myocardium; Organ Size; ortho-Aminobenzoates; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Ventricular Function, Left

Topics: Animals; Body Weight; Dogs; Female; Male; Mice; ortho-Aminobenzoates; Rabbits; Rats; Species Specificity

Topics: Adult; Body Weight; Humans; Male; Nephrotic Syndrome; Obesity; ortho-Aminobenzoates; Proteinuria