Inhibitory effects of rosmarinic acid on the proliferation of cultured murine mesangial cells. (1/90)

BACKGROUND: Rosmarinic acid is a phenolic compound widely distributed in Labiatae herbs such as rosemary, sweet basil, and perilla, which are frequently used with meat and fish dishes in Western and Asian countries. In the present study we investigated the effects of rosmarinic acid on cultured murine mesangial cell proliferation. METHODS: Cultured murine mesangial cells were stimulated by growth factors with or without rosmarinic acid, and [(3)H]thymidine incorporation was measured in regard both to signal transduction and to cell cycle dependency. In other experiments, mRNA extracted from the cells was analysed by Northern blotting. RESULTS: Rosmarinic acid inhibited the cell proliferation induced by platelet-derived growth factor (PDGF) (P<0.01; IC(50) values, 1.4 microg/ml) or tumour necrosis factor-alpha (P<0.01; IC(50) values, 3. 8 microg/ml), and these effects involved both the G(0)/G(1) and G(1)/S phases of the cell cycle. Rosmarinic acid also suppressed the mRNA expressions of PDGF and c-myc in PDGF-stimulated mesangial cells. CONCLUSIONS: Rosmarinic acid inhibits cytokine-induced mesangial cell proliferation and suppresses PDGF and c-myc mRNA expression in PDGF-stimulated mesangial cells. Rosmarinic acid in Labiatae herbs might be a promising agent to prevent mesangial cell proliferation.  (+info)

Effect of oral treatment of Perilla frutescens and its constituents on type-I allergy in mice. (2/90)

Perilla frutescens Britton (perilla, Labiatae) is a medicinal herb prescribed in Saiboku-to [Japanese letters: see text], which is a Kampo formula effective for allergic diseases such as bronchial asthma. The present study was conducted to evaluate the anti-allergic effect of orally administered perilla decoction and to identify the active constituents using mice ear-passive cutaneous anaphylaxis (PCA)-reaction, which is one of the animal models for type I allergy. Perilla decoction significantly suppressed PCA-reaction, and the inhibition % at the dose of 500 mg/kg was 43%. The perilla decoction contains 5.3% of luteolin 7-O-[beta-glucuronosyl(2-->1)beta-glucuronide], 1.6% of apigenin 7-O-[beta-glucuronosyl(2-->1)beta-glucuronide], 0.49% of scutellarin, and 2.5% of rosmarinic acid (weight of compound/dried weight of perilla decoction %), respectively. When these constituents were orally administered to mice at the dose equivalent to 500 mg/kg of perilla decoction, rosmarinic acid and apigenin 7-O-[beta-glucuronosyl(2-->1)beta-glucuronide] significantly suppressed PCA-reaction, and their inhibition % was 41% (p<0.01) and 32% (p<0.05), respectively. Since the inhibition % or perilla decoction and rosmarinic acid were nearly equal, the anti-allergic effect of perilla decoction depends primarily on rosmarinic acid. The standard Saiboku-to decoction contained 0.013% of rosmarinic acid, which was too low to exhibit anti-allergic activity in a daily dose of Saiboku-to in adults, suggesting that perilla would be prescribed in Saiboku-to to exhibit other pharmacological effects than its anti-allergic activity, such as a sedative.  (+info)

Synthesis of 2-O-(4-coumaroyl)-3-(4-hydroxyphenyl)lactic acid, an important intermediate of rosmarinic acid biosynthesis. (3/90)

A simple method to synthesize (+/-)-2-O-(4-coumaroyl)-3-(4-hydroxyphenyl)lactic acid (1), a key intermediate in rosmarinic acid biosynthesis in higher plant cells, was established by condensation of protected 4-coumaric acid and (+/-)-3-(4-hydroxyphenyl)lactic acid followed by deprotection. A stable supply of 1 thus attained will lead to biochemical and molecular biological characterization of later steps of rosmarinic acid biosynthesis.  (+info)

CYP98A6 from Lithospermum erythrorhizon encodes 4-coumaroyl-4'-hydroxyphenyllactic acid 3-hydroxylase involved in rosmarinic acid biosynthesis. (4/90)

Rosmarinic acid is the dominant hydroxycinnamic acid ester accumulated in Boraginaceae and Lamiaceae plants. A cytochrome P450 cDNA was isolated by differential display from cultured cells of Lithospermum erythrorhizon, and the gene product was designated CYP98A6 based on the deduced amino acid sequence. After expression in yeast, the P450 was shown to catalyze the 3-hydroxylation of 4-coumaroyl-4'-hydroxyphenyllactic acid, one of the final two steps leading to rosmarinic acid. The expression level of CYP98A6 is dramatically increased by addition of yeast extract or methyl jasmonate to L. erythrorhizon cells, and its expression pattern reflected the elicitor-induced change in rosmarinic acid production, indicating that CYP98A6 plays an important role in regulation of rosmarinic acid biosynthesis.  (+info)

Regulation of lithospermic acid B and shikonin production in Lithospermum erythrorhizon cell suspension cultures. (5/90)

Cell suspension cultures of Lithospermum erythrorhizon produced a large amount of lithospermic acid B, a caffeic acid tetramer, as well as shikonin derivatives (each ca. 10% of dry wt.) when cultured in shikonin production medium M-9. Various culture factors for increasing the production of lithospermic acid B were investigated. Lithospermic acid B production was inhibited by 2, 4-D or NH4+, whereas it was stimulated by Cu2+. These regulatory patterns were similar to those for the production of shikonin derivatives in these cell cultures, suggestive of close relations and similar metabolic regulation between the production of these compounds. Cultivation under light illumination, however, showed that these metabolisms were independently regulated. In particular, blue light showed a stimulatory effect on lithospermic acid B production, while shikonin production was strongly inhibited, indicative of an effective condition for lithospermic acid B production.  (+info)

Differential production of meta hydroxylated phenylpropanoids in sweet basil peltate glandular trichomes and leaves is controlled by the activities of specific acyltransferases and hydroxylases. (6/90)

Sweet basil (Ocimum basilicum) peltate glandular trichomes produce a variety of small molecular weight phenylpropanoids, such as eugenol, caffeic acid, and rosmarinic acid, that result from meta hydroxylation reactions. Some basil lines do not synthesize eugenol but instead synthesize chavicol, a phenylpropanoid that does not contain a meta hydroxyl group. Two distinct acyltransferases, p-coumaroyl-coenzyme A:shikimic acid p-coumaroyl transferase and p-coumaroyl-coenzyme A:4-hydroxyphenyllactic acid p-coumaroyl transferase, responsible for the production of p-coumaroyl shikimate and of p-coumaroyl 4-hydroxyphenyllactate, respectively, were partially purified and shown to be specific for their substrates. p-Coumaroyl-coenzyme A:shikimic acid p-coumaroyl transferase is expressed in basil peltate glands that are actively producing eugenol and is not active in glands of noneugenol-producing basil plants, suggesting that the levels of this activity determine the levels of synthesis of some meta-hydroxylated phenylpropanoids in these glands such as eugenol. Two basil cDNAs encoding isozymes of cytochrome P450 CYP98A13, which meta hydroxylates p-coumaroyl shikimate, were isolated and found to be highly similar (90% identity) to the Arabidopsis homolog, CYP98A3. Like the Arabidopsis enzyme, the basil enzymes were found to be very specific for p-coumaroyl shikimate. Finally, additional hydroxylase activities were identified in basil peltate glands that convert p-coumaroyl 4-hydroxyphenyllactic acid to its caffeoyl derivative and p-coumaric acid to caffeic acid.  (+info)

Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-gamma 1 and Itk activity. (7/90)

Rosmarinic acid (RosA) is a hydroxylated compound frequently found in herbal plants and is mostly responsible for anti-inflammatory and antioxidative activity. Previously, we observed that RosA inhibited T-cell antigen receptor (TCR)- induced interleukin 2 (IL-2) expression and subsequent T-cell proliferation in vitro. In this study, we investigated in detail inhibitory mechanism of RosA on TCR signaling, which ultimately activates IL-2 promoter by activating transcription factors, such as nuclear factor of activated T cells (NF-AT) and activating protein-1 (AP-1). Interestingly, RosA inhibited NF-AT activation but not AP-1, suggesting that RosA inhibits Ca(2+)-dependent signaling pathways only. Signaling events upstream of NF-AT activation, such as the generation of inositol 1,4,5-triphosphate and Ca(2+) mobilization, and tyrosine phosphorylation of phospholipase C-gamma 1 (PLC-gamma 1) were strongly inhibited by RosA. Tyrosine phosphorylation of PLC-gamma 1 is largely dependent on 3 kinds of protein tyrosine kinases (PTKs), ie, Lck, ZAP-70, and Itk. We found that RosA efficiently inhibited TCR-induced tyrosine phosphorylation and subsequent activation of Itk but did not inhibit Lck or ZAP-70. ZAP-70-dependent signaling pathways such as the tyrosine phosphorylation of LAT and SLP-76 and serine/threonine phosphorylation of mitogen-activated protein kinases (MAPKs) were intact in the presence of RosA, confirming that RosA suppresses TCR signaling in a ZAP-70-independent manner. Therefore, we conclude that RosA inhibits TCR signaling leading to Ca(2+) mobilization and NF-AT activation by blocking membrane-proximal events, specifically, the tyrosine phosphorylation of inducible T cells kinase (Itk) and PLC-gamma 1.  (+info)

Suppressive effects of Perilla frutescens on IgA nephropathy in HIGA mice. (8/90)

BACKGROUND: Perilla frutescens (perilla) is a herbal medicine used in Japanese traditional Kampo medicine. The present study was conducted to evaluate the anti-nephritic effects of perilla in HIGA mice that spontaneously develop high levels of serum immunoglobulin A (IgA) along with mesangial IgA deposition. METHODS: A perilla decoction and its major active constituent, rosmarinic acid (RsA), were orally administrated to 10-week-old HIGA mice for 16 weeks. At study completion, we measured proteinuria and serum IgA levels and generated histological scores from kidney specimens. In addition, we measured concentrations of IgA in culture media of intestinal Peyer's patch cells and spleen cells obtained from the HIGA mice. RESULTS: Perilla suppressed proteinuria, proliferation of glomerular cells, serum levels of IgA, glomerular IgA and IgG depositions in HIGA mice. Cultured Peyer's patch cells and spleen cells from perilla-treated mice produced significantly less IgA than controls. Rosmarinic acid, by itself, suppressed serum IgA levels and glomerular IgA deposition in HIGA mice. Cultured spleen cells from RsA-treated mice produced less IgA than controls. CONCLUSIONS: The perilla decoction may suppress IgA nephropathy, in part, through modulation of the intestinal mucosal immune system. These effects were caused by RsA acting synergistically with other constituents.  (+info)

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