Role of Carnosic Acid in Protection of Brain Mitochondria
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Carnosic acid (CA; C20H28O4) is characterized as a phenolic diterpene and is a major component of the Rosmarinus officinalis L. (known as rosemary or “alecrim”) (Fig. 1) and Salvia officinalis L. (salvia) plants [176]. CA is an ortho-dihydroquinone-type molecule that produces an electrophilic compound after some free radical-dependent reactions [177]. The conversion of a pro-electrophilic to an electrophilic quinone leads to the interaction of CA with the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which is considered a master regulator of the redox environment in mammalian cells [177–179]. There is evidence that electrophilic agents reacts with some cysteines in the Keap1 protein, leading to the release of Nrf2 from the Nrf2-Keap1 complex and the consequent migration of Nrf2 to the cell nucleus [180–182]. Nrf2 binds to the ARE region of phase II detoxification enzymes, as well as to the ARE region in the genes of antioxidant enzymes [183,184]. Moreover, CA is also a direct antioxidant molecule due to the presence of two O-phenolic hydroxyl moieties in C11 and C12 [185,186].
Inhibiting the Absorption of Dietary Carbohydrates and Fats with Natural Products
Christophe Wiart in Medicinal Plants in Asia for Metabolic Syndrome, 2017
Ethanol extract from leaves of Salvia officinalis L. given orally to type 2 diabetic patients at a dose of 500 mg 3 times per day for 3 months decreased fasting plasma glucose by 25.8%, total cholesterol by 17.7%, triglycerides by 32.2%, low density lipoprotein-cholesterol by 19.2%, and increased high-density lipoprotein-cholesterol by 34.8%.221 Carnosic acid, carnosol, royleanonic acid, 7-methoxyrosmanol, and oleanolic acid isolated from Salvia officinalis L. inhibited porcine pancreatic lipase with IC50 values below 85 μg/mL.222 In ddY mice, carnosic acid at a single oral dose of 20 mg/kg 30 minutes before oral loading of olive oil, reduced 2 hours serum triglycerides from 571 to 220 mg/100 mL (orlistat: 177 mg/100 mL) whereby carnosol, royleanonic acid, 7-methoxyrosmanol, and oleanolic acid up to 200 mg/kg had no effect.222 Carnosic acid given orally at a dose of 10 mg/kg/day for 14 days to ddY mice on high-fat diet, had no effect on body weight, decreased serum triglycerides from 126 to 78 mg/100 mL (normal: 118 mg/100 mL) and decreased epididymal fat pad from 1472 mg/mouse to 1018 mg/mouse (normal: 839 mg/mouse).222 The consumption of sage tea could be beneficial in metabolic syndrome.
An Overview of the NIAID/NIH Chemical Medical Countermeasures Product Research and Development Program *
Brian J. Lukey, James A. Romano, Salem Harry in Chemical Warfare Agents, 2019
Through NIH support, several small and large animal models of intoxication by metabolic poisons have been developed and validated over the past decades. In vivo models have ranged from small, such as rodents and rabbits (Crankshaw et al., 2007;Cronican et al., 2015; Lee et al., 2008), to large animals such as swine and sheep (Bebarta et al., 2014; Bhandari et al., 2014; Haouzi et al., 2015). Using these models, a number of compounds have demonstrated efficacy in promoting overall survival after exposure. These promising compounds include: dimethyl trisulfide (DMTS), methylene blue, cobinamide, methemoglobin, sodium nitrite, and sulfanegen (Chan et al., 2015; Chenuel et al., 2015; Cronican et al., 2015; Judenherc-Haouzi et al., 2016; Kovacs et al., 2016; Nagasawa et al., 2007). The mechanistic action of most of the identified therapies is to either scavenge or detoxify the target chemical threat by metabolism while it is still in circulation before cellular respiration is severely affected. When removal from the circulatory system is not possible, attempts at mitigating the potential chronic or longer-term neurological impacts of intoxication have identified carnosic acid, a pro-electrophilic compound, as a viable therapy (for cyanide poisoning). Carnosic acid is hypothesized to protect the brain by specifically upregulating central antioxidant enzymes to reduce the neuronal cell loss that commonly occurs after seizure activity (Zhang et al., 2015). While most of the efficacy demonstrated to date has been for either hydrogen sulfide or cyanide, the vitamin B12 analog cobinamide has been shown to enhance survival after poisoning by both of those chemicals (Bebarta et al., 2014; Brenner et al., 2014).
Comparison of the Protective Effect of Salvia officinalis and Rosmarinus officinalis Infusions Against Hepatic Damage Induced by Hypotermic-Ischemia in Wistar Rats
Published in Nutrition and Cancer, 2020
Sana Bahri, Ridha Ben Ali, Raed Abdennabi, Dorra Ben Said, Mona Mlika, Mohamed Kacem Ben Fradj, Michelle Véronique El May, Saloua Ben Khamsa Jameleddine
Otherwise, HPLC analysis showed also that carnosic and rosmarinic acids’ levels in R. officinalis L. infusion are practically similar (29.27 vs. 31.28 mg/L, respectively). In contrast, the content of rosmarinic acid is slightly higher than that of carnosic acid in S. officinalis L. infusion (39.35 vs. 28.43 mg/L, respectively). Carnosic acid was reported to play an antioxidant, anti-inflammatory, and anticancer activities among others (28). Rosmarinic acid was also described to play the role of an antimicrobial, immunomodulatory, antidiabetic, antiallergic, anti-inflammatory, anticancer, hepato- and renal-protectant agent among others (29). Together, carnosic acid and rosmarinic acid were reported to play an antifibrotic and andioxidative effects due to their synergistic pro-apoptotic action on lung fibroblasts and myofibroblasts (30). The presence of these compounds both in S. officinalis L. and R. officinalis L. infusion can also boost the protective effects observed by the treatment of these two medicinal plants.
Bioactivation of herbal constituents: mechanisms and toxicological relevance
Published in Drug Metabolism Reviews, 2019
Rosmarinic acid, carnosic acid and carnosol are the major biological active compounds in rosemary (Rosmarinus officinalis) (Figure 11(j)). They have a variety of pharmacological activities including antioxidant, antiallergic, anti-inflammatory, and anticarcinogenic effects (Petersen and Simmonds 2003). Two-electron oxidation of rosmarinic acid produces electrophilic ortho-quinones leading to formation of GSH conjugates and covalent modification of a variety of cellular proteins mainly at cysteine residues (Tang et al. 2015: Tang et al. 2016). Rosmarinic acid ortho-quinones likely suppressed NF-κB activation through inhibition of MAPKs/IKK activity and activated Keap1/Nrf2 signaling pathways via covalent modification of Keap1 cysteine residues, which led to protection from lipopolysaccharide/D-galactosamine-induced acute liver injury in mice (Li, Feng, Wang, et al. 2019). Similarly, the neuroprotective activity of carnosic acid was attributed to activation of the Keap1/Nrf2/ARE pathway via S-alkylation of targeted cysteines on Keap1 by the carnosic acid ortho-quinone (Satoh et al. 2008). Similarly, carnosol is a potent inducer of cytoprotective enzymes likely through carnosol ortho-quinone mediated modulation of the Keap1/Nrf2/ARE pathway (Wu et al. 2014). Covalent adduction of the cysteine thiols of Keap1 protein (i.e. cysteine 151 of Keap1) by these quinone intermediates results in release of Nrf2 protein from the Keap1/Nrf2 complex leading to Nrf2 translocation into the nucleus, where it activates transcription of cytoprotective enzymes such as NQO1, HO-1 and GST via ARE transcriptional elements (Satoh et al. 2008; Wu et al. 2014).
Genomics of Detoxification: How Genomics can be Used for Targeting Potential Intervention and Prevention Strategies Including Nutrition for Environmentally Acquired Illness
Published in Journal of the American College of Nutrition, 2020
Sharon R. Hausman-Cohen, Lee J. Hausman-Cohen, Grant E. Williams, Carol E. Bilich
In cases of partial or complete loss of function of NQO1, a few interventions have been noted to help reduce damage from benzenes. The most ideal interventions seem to involve restoring NQO1 function to normal levels. Particularly in heterozygotes expressing half function, sulforaphane (broccoli, kale, cabbage, etc.) in moderation has been demonstrated to restore apparent full function in in vitro studies (43). Similar effects have been demonstrated in response to carnosic acid, commonly found in rosemary (44), and alpha lipoic acid (45). Furthermore, sulforaphane and alpha lipoic acid have been shown directly to diminish the effects of benzene toxicity, confirming the biological significance to the upregulation of NQO1. Further studies on the benzene-protective effects of carnosic acid are thus warranted, but currently no such effect has been demonstrated. What these supplements have in common is an apparent activation of the Nrf2 pathway upstream of NQO1 (43–45)—providing a target of upregulation that may be addressed by yet other supplements or dietary changes. However, it is unclear if these interventions can restore sufficient function in the cases of those with variants in both copies of the gene, and so in those rare cases extra care should be taken to avoid benzenes. For these individuals with partially or fully impaired NQO1 pathways, there may be benefit found in pushing glutathione pathways or providing oral glutathione. One intermediate metabolite of benzene (benzene oxide) has been demonstrated to conjugate with glutathione for efficient removal and deactivation of this product (46) however this has not yet been studied as a sufficient mechanism in terms of significantly alleviating benzene toxicity.