Carnosol

Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary.[Pubmed: 22173778 ]

Eur J Nutr. 2013 Feb;52(1):85-95.

The use of rosemary (Rosmarinus officinalis) leaves and their constituents as a source of dietary antioxidants and flavoring agents is continuously growing. Carnosol and carnosic acid, two major components of rosemary extracts, have shown activity for cancer prevention and therapy. In this study, we investigate the cytotoxic and anti-angiogenic activities of Carnosol and carnosic acid, in order to get further insight into their mechanism of action.
METHODS AND RESULTS:
Our results demonstrate that the mentioned diterpenes inhibit certain functions of endothelial cells, namely, differentiation, proliferation, migration and proteolytic capability. Our data indicate that their growth inhibitory effect, exerted on proliferative endothelial and tumor cells, could be due to, at least in part, an induction of apoptosis. Inhibition of the mentioned essential steps of in vitro angiogenesis agrees with the observed inhibition of the in vivo angiogenesis, substantiated by using the chick chorioallantoic membrane assay.
CONCLUSIONS:
The anti-angiogenic activity of Carnosol and carnosic acid could contribute to the chemopreventive, antitumoral and antimetastatic activities of rosemary extracts and suggests their potential in the treatment of other angiogenesis-related malignancies.

Antimicrobial activity of carnosol and ursolic acid: two anti-oxidant constituents of Rosmarinus officinalis L.[Reference: WebLink]

Food Microbiol., 1987, 4(4):311-5.

METHODS AND RESULTS:
Inhibition of the growth of 6 strains of food associated bacteria and yeasts by Carnosol and Ursolic acid, two antioxidant compounds extracted from rosemary, was investigated and compared to inhibitory effects exhibited by the commonly used food antioxidants Butylated Hydroxyanisole (BHA) and Butylated Hydroxytoluene (BHT). At the highest concentration used (150 μg ml−1) Carnosol inhibited all the test microbes to the greatest extent. BHA proved a superior inhibitor to Ursolic acid which itself was more effective overall than BHT. Even at 50 μg ml−1, Carnosol caused a significant decrease in both bacterial and yeast growth whilst BHA proved more effective against the yeasts than bacteria.
CONCLUSIONS:
Thus Carnosol might prove useful as a food antioxidant which could also contribute to the retardation of the microbial spoilage of foods.

Protective effect of carnosol on CCl(4)-induced acute liver damage in rats.[Pubmed: 12352220]

Eur J Gastroenterol Hepatol. 2002 Sep;14(9):1001-6.

We recently reported that (Lamiaceae) may alleviate CCl(4)-induced acute hepatotoxicity in rats, possibly blocking the formation of free radicals generated during CCl(4) metabolism. Carnosol, one of the main constituents of Rosmarinus, has been shown to have antioxidant and scavenging activities. Therefore, it is plausible to expect that Carnosol may mediate some of the effects of Rosmarinus on oxidative stress consequences induced by CCl(4) in the liver. We evaluated the effectiveness of Carnosol to normalize biochemical and histological parameters of CCl(4)-induced acute liver injury.
METHODS AND RESULTS:
Male Sprague Dawley rats (n = 5) injured by CCl(4) (oral dose 4 g/kg of body weight) were treated with a single intraperitoneal dose (5 mg/kg) of Carnosol. Twenty-four hours later, the rats were anaesthetized deeply to obtain the liver and blood, and biochemical and histological parameters of liver injury were evaluated. Carnosol normalized bilirubin plasma levels, reduced malondialdehyde (MDA) content in the liver by 69%, reduced alanine aminotransferase (ALT) activity in plasma by 50%, and partially prevented the fall of liver glycogen content and distortion of the liver parenchyma.
CONCLUSIONS:
Carnosol prevents acute liver damage, possibly by improving the structural integrity of the hepatocytes. To achieve this, Carnosol could scavenge free radicals induced by CCl(4), consequently avoiding the propagation of lipid peroxides. It is suggested that at least some of the beneficial properties of Rosmarinus officinalis are due to Carnosol.

Identification of natural compound carnosol as a novel TRPA1 receptor agonist.[Pubmed: 25405290]

Carnosic acid and carnosol inhibit adipocyte differentiation in mouse 3T3-L1 cells through induction of phase2 enzymes and activation of glutathione metabolism.[Pubmed: 19289108]

Biochem Biophys Res Commun. 2009 May 8;382(3):549-54.

METHODS AND RESULTS:
In the previous studies, we reported that carnosic acid (CA) and Carnosol (CS) originating from rosemary protected cortical neurons by activating the Keap1/Nrf2 pathway, which activation was initiated by S-alkylation of the critical cysteine thiol of the Keap1 protein by the "electrophilic"quinone-type of CA or CS. Here, we found that CA and CS inhibited the in vitro differentiation of mouse preadipocytes, 3T3-L1 cells, into adipocytes. In contrast, other physiologically-active and rosemary-originated compounds were completely negative. These actions seemed to be mediated by activation of the antioxidant-response element (ARE) and induction of phase2 enzymes. This estimation is justified by our present findings that only CA and CS among rosemary-originated compounds significantly activated the ARE and induced the phase2 enzymes. Next, we performed cDNA microarray analysis in order to identify the gene(s) responsible for these biological actions and found that phase2 enzymes (Gsta2, Gclc, Abcc4, and Abcc1), all of which are involved in the metabolism of glutathione (GSH), constituted 4 of the top 5 CA-induced genes. Furthermore, CA and CS, but not the other compounds tested, significantly increased the intracellular level of total GSH.
CONCLUSIONS:
Thus, we propose that the stimulation of GSH metabolism may be a critical step for the inhibition of adipocyte differentiation in 3T3-L1 cells and suggest that pro-electrophilic compounds such as CA and CS may be potential drugs against obesity-related diseases.

Molecules. 2014 Nov 14;19(11):18733-46.

The transient receptor potential ankyrin 1 (TRPA1) cation channel is one of the well-known targets for pain therapy. Herbal medicine is a rich source for new drugs and potentially useful therapeutic agents. To discover novel natural TRPA1 agonists, compounds isolated from Chinese herbs were screened using a cell-based calcium mobilization assay.
METHODS AND RESULTS:
Out of the 158 natural compounds derived from traditional Chinese herbal medicines, Carnosol was identified as a novel agonist of TRPA1 with an EC50 value of 12.46 μM. And the agonistic effect of Carnosol on TRPA1 could be blocked by A-967079, a selective TRPA1 antagonist. Furthermore, the specificity of Carnosol was verified as it showed no significant effects on two other typical targets of TRP family member: TRPM8 and TRPV3. Carnosol exhibited anti-inflammatory and anti-nociceptive properties; the activation of TRPA1 might be responsible for the modulation of inflammatory nociceptive transmission.
CONCLUSIONS:
Collectively, our findings indicate that Carnosol is a new anti-nociceptive agent targeting TRPA1 that can be used to explore further biological role in pain therapy.

Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages.[Pubmed: 12082020]

Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappa B and c-Jun.[Pubmed: 15627474]

Biochem Pharmacol. 2005 Jan 15;69(2):221-32.

Carnosol, a constant constituent of Rosmarinus officinalis extracts, is a phenolic diterpene shown to have antioxidant and anticarcinogen properties.
METHODS AND RESULTS:
In our studies, Carnosol inhibited the invasion of highly metastatic mouse melanoma B16/F10 cells in vitro. First, the antimetastatic potentials of Carnosol were examined by soft agar colony formation assay. Second, Carnosol dose-dependently inhibited B16/F10 cell migration and invasion by in vitro transwell assay. Third, the decreasing activity of metalloproteinase was observed by zymographic assay. The result revealed that the treatment of Carnosol could diminish the activity of MMP-9 more than MMP-2. Next, we analyzed the amounts of MMP-9 and MMP-2 proteins in the cells. The data indicated MMP-9 protein was also suppressed by Carnosol in the same manner. In accordance with the above data, the results of reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed a reduced level of MMP-9 mRNA. Furthermore, Carnosol significantly inhibited the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, AKT, p38, JNK and inhibition of activation of transcription factors NFkappa-B and c-Jun. These results lead us to conclude that Carnosol could restrict the invasive ability of B16/F10 mouse melanoma cells by reducing MMP-9 expression and activity through suppressing (ERK) 1/2, AKT, p38, and JNK signaling pathway and inhibition of NF-kappaB and AP-1 binding activity.
CONCLUSIONS:
Taken together, these results indicate that Carnosol targets MMP-mediated cellular events in cancer cells and provides a new mechanism for its anticancer activity.

Carcinogenesis. 2002 Jun;23(6):983-91.

Carnosol is a naturally occurring phytopolyphenol found in rosemary. Carnosol functions as antioxidant and anticarcinogen. In the present study, we compared the antioxidant activity of Carnosol and other compounds extracted from rosemary.
METHODS AND RESULTS:
Carnosol showed potent antioxidative activity in alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) free radicals scavenge and DNA protection from Fenton reaction. High concentrations of nitric oxide (NO) are produced by inducible NO synthase (iNOS) in inflammation and multiple stages of carcinogenesis. Treatment of mouse macrophage RAW 264.7 cell line with Carnosol markly reduced lipopolysaccharide (LPS)-stimulated NO production in a concentration-related manner with an IC50 of 9.4 microM; but other tested compounds had slight effects. Western blot, reverse transcription-polymerase chain reaction, and northern blot analyses demonstrated that Carnosol decreased LPS-induced iNOS mRNA and protein expression. Carnosol treatment showed reduction of nuclear factor-kappaB (NF-kappaB) subunits translocation and NF-kappaB DNA binding activity in activated macrophages. Carnosol also showed inhibition of iNOS and NF-kappaB promoter activity in transient transfection assay. These activities were referred to down-regulation of inhibitor kappaB (IkappaB) kinase (IKK) activity by Carnosol (5 microM), thus inhibited LPS-induced phosphorylation as well as degradation of IkappaBalpha. Carnosol also inhibited LPS-induced p38 and p44/42 mitogen-activated protein kinase (MAPK) activation at a higher concentration (20 microM).
CONCLUSIONS:
These results suggest that Carnosol suppresses the NO production and iNOS gene expression by inhibiting NF-kappaB activation, and provide possible mechanisms for its anti-inflammatory and chemopreventive action.