Rosmarinus Officinalis Extract

Rosemary extracts contain many bioactive components including phenolic mono-terpenes (α-pinene, camphene, limonene) [13], diterpenes (carnosic acid, carnosol), flavones (genkwanin, isoscutellarein 7-O-glucoside), and caffeolyl derivatives (rosmarinic acid).

From: Complementary and Alternative Therapies and the Aging Population, 2009

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Health Benefits of Traditional Culinary and Medicinal Mediterranean Plants

Stephanie C. Degner, ... Donato F. Romagnolo, in Complementary and Alternative Therapies and the Aging Population, 2009

Rosemary

Rosemary (Rosmarinus officinalis Linn. Family Labiatae) is a perennial plant native of the Mediterranean area. Rosemary extracts are used routinely for cooking, preservation of foods, cosmetics, or in herbal medicine for anti-inflammatory and antimicrobial applications [9, 10], and for the prevention and treatment of diabetic and cardiovascular diseases [11]. At least 30 components have been identified in essential oils, which have been shown to possess olfactory properties that influence cognitive performance including memory [12]. Rosemary extracts contain many bioactive components including phenolic mono-terpenes (α-pinene, camphene, limonene) [13], diterpenes (carnosic acid, carnosol), flavones (genkwanin, isoscutellarein 7-O-glucoside), and caffeolyl derivatives (rosmarinic acid). The highest accumulation of these groups of compounds occurs in leaves and it is related to young stages of plant development [14]. In general, rosmarinic acid is present at the highest concentration in all rosemary plant organs. Carnosic acid and carnosol are found in stems during young stages, but their concentrations decrease in the vascular system following aging. However, high levels of phenolic diterpenes and rosmarinic acid are found in flowers as a result of in situ biosynthesis and transport from other plant organs. Rosemary extracts in both aqueous and lipid medium have been shown to possess antioxidant activity, which is due to the presence of a catechol group in the aromatic ring of the phenolic terpenes, and cathecols conjugated with a carboxylic acid group in rosmarinic acid. Interestingly, rosmarinic acid is more effective as antioxidant in bulk oil whereas carnosol and carnosic acid perform better in oil-in-water emulsions. These differences in antioxidant efficacy have been attributed to interfacial partitioning of these compounds [15].

Many studies have investigated the health benefits of extracts from rosemary plants and documented that extracts exhibited protective effects against oxidative damage to DNA by scavenging hydroxyl and singlet oxygen radicals [16], and prevented the activation of carcinogens by members of P450 family of metabolizing enzymes while increasing detoxification [17, 18]. Aqueous extracts of the young sprouts of rosemary were found to exert anti-lipoperoxidant activity, and protected against radiation-induced hepatotoxicity in Swiss albino mice [19]. Similarly, the oral administration (250 mg/kg body weight) of rosemary extracts to male Sprague-Dawley rats reduced tetrachloride-induced acute hepatotoxicity [20]. Moreover, dietary rosemary extracts at doses ranging from 0.5% to 1.0% were reported to suppress the binding of dimethyl-benz[a]anthracene (DMBA) metabolites to DNA in female Sprague-Dawley rats [21, 22], DNA damage by the carcinogen benzo[a]pyrene [23], and at doses of 500 mg/kg body weight DMBA-induced skin tumors in mice [24]. Extracts of rosemary have also been shown to possess antiviral effects against Herplex simplex [25] and inhibited the growth of the gram-negative bacterium Helicobacter pylori, which is recognized as the primary etiological factor in the development of gastritis and peptic ulcer disease [26]. In association with vitamin D3, rosemary preparations and carnosic acid enhanced differentiation of HL60 cells in vitro and exerted antileukemic activity in Balb/c mice [27]. A recent study that screened herb extracts for antithrombotic effects in vitro and in a mouse model reported that rosemary along with thyme extracts showed significant antithrombotic activity possibly through an inhibitory effect on platelet reactivity [28]. Interestingly, the same study reported that the anti-platelet activity of rosemary was heat-stable suggesting that the active components may remain preserved after cooking.

Rosmarinic acid, which was first isolated from Rosmarinus officinalis by two Italian scientists [29], is an esterification product of caffeic acid which originates from the amino acid phenylalanine, and 3,4-dihydroxyphenyllactic acid which is produced from tyrosine [30]. However, other medicinal herbs have been shown to contain rosmarinic acid including lemon balm (Melissa officinalis), sage (Salvia officinalis, Salvia aegyptiaca L.), olives (Olea europea L), tobacco (Nicotiana tabacuum), and peppermint (Mentha piperita L.) [31]. In plants, rosmarinic acid may exert a protective role against pathogens and herbivores. In humans, rosmarinic acid is absorbed, conjugated, and methylated in the intestine and liver and it is present in plasma and urine in a conjugated form (glucuronide and/or sulfated). Metabolites of rosmarinic acid have been shown to be excreted within few hours [32, 33].

Studies have investigated in animal models the biological activity of rosmarinic acid and reported that it inhibited epidermal inflammatory responses by reducing neutrophil infiltration, myeloperoxidase activity, cyclooxygenase-2 mRNA expression, and reactive oxygen radical production [34]. In humans, rosmarinic acid reduced the incidence of allergic rhinoconjunctivitis by inhibiting the inflammatory response and scavenging of reactive oxygen species (ROS) [35, 36]. Recent studies have documented that rosmarinic acid inhibited a number of processes involved in angiogenesis and ROS-associated VEGF expression and Il-8 release [37].

Several studies have investigated the mechanisms of action of rosmarinic acid. In B16 melanoma cells, it induced melanin synthesis (melanogenesis) through activation of CREB via PKA signaling in a cAMP-independent manner [38]. Other effects of rosmarinic acid included protection against adriamycin-induced apoptosis in H9c2 cardiac muscle cells [39] and inhibition of Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling [40].

Carnosol and carnosic acid are diterpenes, which contribute to the antioxidant and anti-inflammatory activity of rosemary extracts [41, 42]. In rosemary plants, carnosic acid protects chloroplasts from oxidative stress by scavenging free radicals [43]. Studies documented that carnosol exerted a variety of preventative effects by reducing DMBA-induced rat mammary tumorigenesis and in vivo DMBA–DNA adduct formation [44], skin tumorigenesis [45], the invasion of melanoma cells [46], progression through the cell cycle [47], aflatoxin B1-induced oxidative stress [48], and platelet aggregatation [49]. Both carnosol and carnosic acid have been shown to be activators of the human peroxisome proliferators-activated receptor gamma [50] thus raising the possibility these compounds may exert hypoglycemic and anti-diabetic effects.

Toxicity related to rosemary has been reported for skin applications of rosemary alcohol which induced contact dermatitis in one patient [51]. The dietary administration to Sprague-Dawley rats of rosemary at levels of 500 mg/kg of body weight for 63 days was associated with reduced fertility in females and a decline in spermatogenesis [52]. However, the clinical implications of these results to traditional dietary consumption of rosemary in human populations of the Mediterranean basin remain unknown.

These cumulative data suggest that rosemary extracts contain several bioactive components including phenolic diterpenes, phenolic acids, and flavonoids that may enhance the health benefits of the Mediterranean diet by acting as antioxidants and improving the detoxification systems [20, 53]. Also, rosemary extracts or selected constituents exert anti-inflammatory, anti-thrombotic, and anti-tumor actions [54] which could be exploited for the routine preparation of foods as well as for the development of prophylactic dietary protocols.

Rosemary extracts have been used in a variety of applications. The addition of rosemary to ground chicken had an overall positive effect on raw meat appearance during storage and cooked meat flavor, and improved redness [55]. Similarly, antioxidant films have been developed to incorporate a natural extract of rosemary and are intended for contact with foods [56]. A study that examined the clinical safety and efficacy of NG440, a phytochemical-based anti-inflammatory formula consisting of a combination of rho iso-alpha acids from hops, rosemary, and oleanolic acid, concluded that NG440 reduced pain scores in patients with joint discomfort suggesting that phytochemical preparations containing rosemary may be used as an alternative to specific COX2 inhibitors [57]. Aromatherapy acupressure in stroke patients with lavender, rosemary, and peppermint exerted a positive effect on hemiplegic shoulder pain compared to acupressure alone [58].

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Carnosic acid and brain mitochondria

Marcos Roberto de Oliveira, in Mitochondrial Physiology and Vegetal Molecules, 2021

3 The mitochondria-related effects induced by CA in ex vivo/in vivo experimental models

It was shown by Romo Vaquero et al. (2013) that CA and its derivatives may be found in different organs (including the brain) of Zucker rats that received a CA-enriched rosemary extract (40%, w/w). Furthermore, CA induced neuroprotection in different in vivo experimental models, indicating that this diterpene easily accesses the brain cells after crossing the BBB. In a mouse model of retinitis pigmentosa, CA reduced the progression of photoreceptor degeneration (Kang et al., 2016). Besides, Miller et al. (2015) have shown that CA exhibited an ability to protect the mouse brain in an experimental model of traumatic brain injury (TBI). Rosemary extract also was efficient in alleviating memory impairment in rats (Ozarowski et al., 2013) and mice (Farr et al., 2016). CA also promoted neuroprotection in mice exposed to cyanide, as reported by Zhang et al. (2015). Nanotechnology-related strategies have been utilized to increase the bioavailability of CA in mammals. Vaka et al. (2011, 2013) demonstrated that a nanoparticle system with CA upregulated neurotrophins in the brain of rats treated by the intranasal route.

Miller et al. (2013) demonstrated that CA (at 1 mg/kg, single i.p. injection) pretreatment (for 48 h) decreased the vulnerability of mitochondria extracted from the mice brain in an ex vivo experimental model using 4-hydroxynonenal (HNE) at 30 μM for 15 min. In this type of experimental model, the animals are administrated with a certain molecule and, after a specific period, the mitochondria are isolated from selected organs and tested in vitro. Thus, this is an ex vivo experimental model: a hybrid of both in vitro and in vivo experimental models to test the vulnerability of the organelles in a given condition. HNE is an intermediate in the lipid peroxidation reactions and causes cellular and mitochondrial dysfunctions (Csala et al., 2015). HNE has been detected in the brain of patients suffering from neurodegenerative diseases and has been viewed as an important player in the onset and progression of those diseases (Yoritaka et al., 1996; Zarkovic, 2003). Using that experimental model, the authors have found that the in vivo administration of CA to the mice prevented the effects induced by HNE in the in vitro assay. CA decreased the inhibitory effect induced by HNE on the activity of the complexes I–II and the levels of HNE-bound protein in the mitochondria. The authors also compared the actions of CA with those induced by sulforaphane and found that both molecules exhibited a very similar effect in the ex vivo experimental model. Importantly, the authors also observed increased levels of HO-1 in the mice cerebral cortex, indicating a possible role for this enzyme in mediating the mitochondria-related protection elicited by CA.

Miller et al. (2015) also reported that CA (1 mg/kg, single i.p. injection) posttreatment (15 min after the lesion) promoted mitochondrial protection in the mice cerebral cortex in an experimental model of TBI. CA induced antioxidant effects and decreased the effects of TBI on the activity of the complexes I–II. Even though the exact mechanism of action by which CA protected mitochondria was not addressed in that work, it is possible that CA upregulated signaling pathways associated with survival and cytoprotection, since CA is not a good antioxidant per se.

Unfortunately, there is a lack of studies demonstrating the effects of CA on the mitochondria in in vivo experimental models focusing on brain cells. It would be necessary performing several studies to better know exactly how CA promotes mitochondrial protection in the mammalian brain. Moreover, experimental models using nanotechnology-related strategies to increase the delivery of CA to brain cells would be welcome. Clinical trials are also another type of experimental model that would improve our knowledge about the effects of CA in the human organism. Therefore, further research is needed and different research groups may interact to find the answers we need regarding the biological actions of CA aiming to improve human life quality and health.

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Pancreatic Cancer, Pancreatitis, and Oxidative Stress

Lin Li, Po Sing Leung, in Gastrointestinal Tissue, 2017

Natural Products From Herbs or Plants

Capsaicin

Capsaicin, a secondary metabolite produced by chili peppers, has been shown to have antipancreatic cancer effects through multiple mechanisms. Zhang et al. demonstrated that capsaicin induced apoptosis through production of ROS and persistent disruption of mitochondrial membrane potential [96]. The oxidation of the mitochondrial lipid cardiolipin and reduction of membrane potential were also involved in capsaicin’s effects. Moreover, the enzymatic activities of catalase and SOD, as well as levels of ATP and GSH in pancreatic cancer were inhibited by capsaicin treatment [97]. Further mechanistic studies demonstrated that capsaicin treatment generated ROS and led to the suppression of Trx and dissociation of Trx-ASK1 interaction, resulting in the activation of mitogen-activated protein kinase kinase (MKK4/MKK7) and their downstream effectors to initiate apoptosis in pancreatic cancer cells. In vivo studies also reported that superoxide and H2O2 levels in tumors of capsaicin-treated mice were increased as compared to controls [98].

Curcumin and Other Curcuminoids

Curcuminoids are natural polyphenol compounds derived from turmeric, which is a member of the ginger family (Zingiberaceae). Among them, curcumin, with bright yellow color, is the principal composition. It has long been used as food, coloring agent, and traditional medicine. A number of preclinical studies have demonstrated anticancer effects of curcumin and other curcuminoids in various types of tumors including pancreatic cancer. Phase I/II clinical trials showed that survival time/rate and quality of life have been improved without cumulative toxicity after oral administration of curcumin alone or in combination with Gem in patients with pancreatic cancer. Since absorption is limited through oral administration, highly bioavailable forms of curcumin such as Theracurmin have been developed for its clinical application [99]. Curcuminoids with ω-3 fatty acids and botanical antioxidants including polyphenols, tocopherols, and rosemary extract induced high caspase-3 activity in pancreatic ductal adenocarcinoma cells and potentiate natural killer cells’ cytocidal function [100]. The mechanistic studies on the anticancer effects of curcuminoids demonstrated that they inhibited cell proliferation through suppression of NF-κB, specificity protein (SP), and antiapoptotic genes, as well as induction of ROS [100,101]. Curcumin, acting as a free radical scavenger and hydrogen donor, exhibits both pro- and antioxidant activities. Multiple signaling pathways are involved in curcumin’s regulatory effects, including NF-κB, Nrf2, STAT3, AKT, MMPs, VEGF, Notch1, Cox-2, ATM/Chk1, WT1, and so on [102,103].

Tea Polyphenols

The chemical composition of tea is quite complex. However, the significant therapeutic properties could be attributed to its polyphenol (flavonoid) components, which are thought to be effective scavengers for reactive oxygen and nitrogen species physiologically. In addition, tea polyphenols act as antioxidants by indirectly regulating NF-κB, activator protein-1, nitric oxide synthase, lipoxygenases, Cox, GST, and SOD [104]. The main flavonoids existing in green tea include catechins, such as (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epicatechin (EC). Catechins are known to inhibit pancreatic cancer by regulating multiple targets such as heat shock proteins, p53, AKT, STAT3, and focal adhesion kinase (FAK). EGCG induced ROS generation and activated JNK, thereby leading to apoptosis in pancreatic cancer cells [103,105]. Green tea catechins and black tea theaflavins seem to downregulate iNOS by inhibiting NF-κB activation. Consistent results showed that in animal models of pancreatic cancer, administration of tea and tea polyphenols prevented carcinogen-induced increase in the oxidized DNA base- 8-OHdG [104]. Although emerging in vitro and in vivo studies indicated tea polyphenols inhibits development and progression of pancreatic cancer, evidence from epidemiologic studies brought disappointment [106]. The fact that catechins are rapidly and extensively metabolized may be responsible for the inconsistent results.

Resveratrol

Resveratrol (trans-3,5,40-trihydroxy-trans-stilbene) has been found in more than 70 plant species including red grapes, peanuts, berries, and pines. Dried roots of Poligonum cuspidatum, an Asian folk medicine, are a rich source of trans-resveratrol, and are used for treating inflammation or hyperlipidemia. Extensive data has proved that resveratrol possesses beneficial effects on various biological processes, including the prevention of cancer and cardiovascular diseases through in vitro and in vivo studies [103]. The antioxidant activity of resveratrol contributed to its anticarcinogentic effects. Various signaling molecules related to pancreatic cancer were targeted by resveratrol, including hedgehog, FOXO, leukotriene A4 hydrolase, macrophage inhibitory cytokine-1, Src, and STAT3. Resveratrol sensitized pancreatic cancer cells to chemotherapeutic agents such as Gem through modulation of drug transporters, NF-κB and STAT3 [103]. Meanwhile, the authors Sun et al. suggested that resveratrol treatment damaged mitochondrial function and led to increased ROS. Furthermore, the ROS were greatly promoted when combined with ionizing radiation [107].

Others

Isothiocyanates, bioactive compounds present in cruciferous vegetables, caused pancreatic cancer cell-cycle arrest, apoptosis, and autophagy by mediating the generation of ROS [108,109]. The excessive production of ROS is partly orchestrated by the depletion of reduced GSH [35]. Daily injection of isothiocyanate sulforaphane decreased the tumor volume by 40% compared with vehicle-treated controls in pancreatic cancer xenograft mouse model [108]. The carbazole alkaloid mahanine derived from edible plants (Murraya koenigii and Micromelum minutum) disrupted the Hsp90-Cdc37 complex as a consequence of ROS generation in MIAPaCa-2 cells [110].

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Herbs and Dementia

Helmut M. Hügel PhD, Neale Jackson PhD, in Diet and Nutrition in Dementia and Cognitive Decline, 2015

Dietary Herbs and Neuroprotection

Since the onset of the neurodegenerative disease process leading to neuronal dysfunction generally predates the first recognition of symptoms by at least 5–10 years, the constant molecular maintenance of a diet could greatly prevent or slow the prevalence of aging-related diseases, cognitive decline, and dementia. Increasing scientific evidence substantiates the cognitive medicinal properties of culinary and dietary herbs. Recent studies show that rosemary extracts have significant inhibitory effects on acetylcholine esterase, a major enzyme associated with several neurological disorders such as Alzheimer’s disease (AD) [5]. Epidemiological and preclinical evidence also suggests that many culinary herbs may have anticancer activities. The consumption of curry powders, mustard, and turmeric has been associated with a lower incidence of colon cancer in some Asian countries. It has been demonstrated that curcumin exerts its anticarcinogenic effects via the p53 tumor repressor gene and various transcription factors and by modulating inflammatory signaling cascades and inducing apoptosis. The antiinflammatory effects and potential cognitive health benefits of curcumin are limited by its low oral bioavailability; therefore regular and long-term dietary supplementation is vital to sustain its neuroprotective effects [6].

Many of the Lamiaceae family of herbs known as mints are widely used culinary herbs, such as peppermint, basil, bay, hyssop, oregano, rosemary, sage, savory marjoram, thyme, lavender, and perilla, which are associated with a long history of medicinal applications. Experiments have indicated that thyme, rosemary, sage, spearmint, and peppermint extracts have inhibitory effects on SW-480 colon cancer cell growth, with sage extracts exhibiting the highest inhibition [7]. Furthermore, evaluation of a standardized extract from the leaves of sage Salvia officinalis specifically indicated that its main ingredient, rosmarinic acid [8], is able to protect cultured rat pheochromocytoma [PC12] cells from multiple β-amyloid peptide-induced neurotoxicity insults, including reactive oxygen species generation, lipid peroxidation, DNA decomposition, caspase- 3 activation, tau protein hyperphosphorylation, and inhibition of phosphorylated p38 mitogen protein kinase activation. In a mouse model, rosmarinic acid at a dose of 0.25 mg/kg protected against the impairment of memory by the β-amyloid (Aβ) peptide through scavenging of the peroxynitrite (ONOO) anion, leading to the implication that daily consumption of culinary herbs containing rosmarinic acid may be chemoprotective against dementia [9]. The utilization of nuclear magnetic resonance (NMR) spectrometer techniques revealed that the binding of rosmarinic acid, a major component of the butanol extract of Salvia sclareoides, to Aβ oligomers [10] inhibited both Aβ oligomerization and deposition [11]. The effect of rosmarinic acid, methyl caffeate, and methyl cinnamate on Aβ peptide aggregation was also evaluated with the thioflavin T (ThT) assay [12], which supported the NMR results and confirmed that these natural compounds, methyl caffeate, methyl cinnamate, and rosmarinic acid, present in many herbs, could have multiple neuroprotective/therapeutic effects against AD.

There is current interest in the investigation of the biological properties of Salvia miltiorrhiza (also known as danshen) in the areas of dementia and AD [13]. A comparative study of the effects of salvianolic acid B (Sal B), the major hydrophilic constituent of the Chinese herb S. miltiorrhiza, and Ginkgo biloba extract EGb 761 on Aβ25-35 fibril formation and cytotoxicity to PC12 cells revealed that both Sal B and EGb 761 inhibited the formation of amyloid fibrils, protected PC12 cells from Aβ25-35 induced cytotoxicity, and also decreased reactive oxygen species (ROS) accumulation caused by Aβ25-35. Significantly, Sal B was much more efficient than EGb 761 in inhibiting Aβ aggregation and in protecting PC12 cells from Aβ-induced cytotoxicity. The protective effects of tanshinone IIA, a lipophilic constituent of S. miltiorrhiza, on the neurotoxicity induced by Aβ protein through calpain and the p35/Cdk5 pathway in primary cortical neurons were also observed. Two other independent studies investigating the neuroprotective capacity of S. miltiorrhiza[13,14] supported these results, indicating that both the water-soluble polyphenol fraction, mainly constituted from caffeic acid (3,4-dihydroxycinnamic acid) monomers and oligomers, and the ethanol extract of tanshinones have multiple biological activities and are the active constituents responsible for the beneficial effects of this Chinese herb for protection against AD. We are using the structural diversity of the caffeic acid derivatives as a molecular scaffold to probe and enhance the significant biological activities found in the major caffeic acid derivatives of S. miltiorrhiza, endeavoring to find potential molecular leads to new drug discovery. Indeed, the reported genetic engineering of danshen has increased the production of rosmarinic acid and lithospermic acid B in S. miltiorrhiza hairy root cultures [15].

Our research and others have identified the individual Chinese herbs that appear most frequently in formulas for dementia ([16–19] and references cited therein). The top five herbs frequently used for dementia and vascular dementia and their bioprofiles are listed in Table 73.1.

Table 73.1. Bioactivity Profiles of Chinese Herbs Used for Dementia Diseases

Herbs Dementia/VaD Neuroprotective Constituents Bioactivity Bioavailability
Polygala tenuifolia Willd. [Dementia] Onjisaponins, A,B,E,F,G tenuifolin Increased BDNF levels in astrocyte cultures; inhibition of Aβ secretion via BACE 1 inhibition Moderate
Poria cocos (Schw.) Wolf [Dementia] Polysaccharides, pachymic acid Hippocampal LTP of synaptic transmission; improved blood circulation Poor
Panax ginseng C.A. Mey [Dementia/VaD] Ginsenosides, protopanaxdiols: Rb1, Rg3, Ginsenoside Rh2 Aβ reductions; neuromodulatory effects; neuronal ATPase Na+/K+ inhibition promoting blood circulation Poor, increased to 30% when combined with P-glycoprotein inhibitor
Acorus gramineus Soland., A. tatarinowii Schott., A. calamus L. [Dementia/VaD] Essential oils: α-, β-asarone, eugenol, monoterpenes, sesquiterpenes Signaling β-asarone: reduction in Aβ-induced JNK activation; downregulation Bcl-w, Bcl-XL proteins; AChE inhibition Good
Rehmannia glutinosa Libosch Catalpol Counters Aβ-induced cholinergic neuron pathology by elevation of BDNF; may be used for improvement of hyperglycemia in diabetic disorders Moderate
[Dementia]
Rhizoma chuanxiong (Chuanxiong) [VaD] Z-ligustilide, 11-angeloylsenkyunolide F Vasorelaxing effects Low oral bioavailability
Radix polygoni Multiflori [VaD] 2,3,5,4-tetrahydroxystilbene-2- O-β-d- glucopyranoside, emodin and physcion Antioxidants Moderate
Radix astragali [VaD] Astragalosides, cycloastragenol Immune function enhancing; telomerase activation Moderate

Listed are the five most frequently used herbs from literature reviews [18,19] of the effectiveness and safety of Chinese herbal medicines for mild cognitive impairment, age-associated memory impairment, and vascular dementia, together with evidence of their bioactivities.

Abbreviations: Aβ, amyloid β; BACE, β-secretase; BDNF, brain-derived neurotrophic factor; JNK, c-Jun N-terminal kinases; LTP, long-term potentiation.

The discovery of the neuroprotective activity of cardiac glycosides against ischemic stroke has stimulated the screening of Chinese herbs used for promoting blood circulation [20]. Based on the steroid glycoside structural similarities between the cardiac glycosides and Chinese herbs, experimental studies have further supported the suggestion that the inhibition of Na+/K+-ATPase in neurons is the common pharmacological action. Interestingly, magnesium lithospermate B (MLB), a major constituent of S. miltiorrhiza bearing no molecular resemblance but having similar structural rigidity, also displayed strong hydrophobic interactions around the binding pocket of Na+/K+-ATPase. Future quality clinical investigations and clinical trials on MLB are needed before its implementation as a safer therapeutic drug than current cardiac glycosides. A proof-of-principle study showed that the oral bioavailability of ginsenoside Rh2 is enhanced to a clinically acceptable level (30%) if P-glycoprotein function is curtailed [21] and the search for safe and effective P inhibitors to combine with ginsenoside Rh2 is under way. Ginseng is one of the most popular herbs in the United States for its use as an adaptogen, to help the body deal with various kinds of stress; it may help boost the immune system and reduce risk of cancer, and it has multifaceted neuroprotective effects for dementia and AD [22]. Dietary herbal beverages for enhancing cognitive function are becoming available. An ultrahigh-temperature (UHT)-treated, low-lactose functional milk containing American ginseng (Panax quinquefolius L.) has been marketed. It is claimed that the consumption of 150–300 mL of this ginseng-enriched milk that contains 11.5–23 mg of ginsenosides is sufficient to improve cognitive function [23]. An extract of the dried roots of P. tenuifolia Willd [BT-11] was investigated as a Korean functional diet. The extract provided cognitive-enhancing verbal memory function for a healthy population [24,25].

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Carnosic acid

Simona Birtić, ... Marc Roller, in Phytochemistry, 2015

7.1 Carnosic acid and carnosol – as the main active antioxidants of food additives in Europe (E392)

Rosemary extracts have been used as antioxidants by the food industry for more than 20 years. The first rosemary extracts used as antioxidants in foods were ingredients derived from oil-soluble, flavourful rosemary oleoresins produced by solvent extraction. Such rosemary extracts were mostly used in savoury applications and labelled as flavours, although primarily used for food preservation purposes.

Identification of carnosic acid (1) as probably the key contributor to the antioxidant activity was an important milestone in the history of the use of rosemary extracts (see Section 7.2). It is considered as a qualitative tracer that allows standardising the antioxidant potency. As deodorised rosemary extracts with an assured content in carnosic acid (1) have become increasingly available since the 1990s, their use for protection from oxidation of a large variety of food matrices significantly increased.

In recognition of their efficiency and upon the request of the food industry, in 2010 rosemary extracts were classified as food additives by the European Commission and assigned the number E392 (Commission Directives 2010/67/EU and 2010/69/EU repealed in 2013 by EU regulation 231/2012 and 1333/2008). “Antioxidant: extracts of rosemary” are to be produced with one of the four extraction processes described in the regulation, by means of solvent extraction (ethanol, acetone or ethanol followed by hexane) or supercritical carbon dioxide extraction, paying respect to purity criteria. According to the EU regulation, only deodorised rosemary extracts containing carnosic acid (1) and carnosol (2) are considered additives. Indeed, carnosic acid (1) and its derivative carnosol (2) are listed as key antioxidant compounds in rosemary extracts and E392 dosage limitations are expressed as levels of carnosic acid (1) and carnosol (2), rather than of the whole rosemary extract. Application areas are food matrices, including oils, animal fats, sauces, bakery wares, meat and fish products etc.

The EU regulation also established a criterion based on the ratio of reference antioxidant compounds (carnosic acid (1) and carnosol (2)) to reference key volatile compounds (main flavouring constituents of rosemary essential oils: borneol, bornyl acetate, camphor, 1,8-cineol, verbenone). It thus gives information on the level of deodorisation of rosemary extracts and on their antioxidative capacities. Antioxidant rosemary extracts must have a content in reference antioxidant compounds that is at least 15 times higher than their content in key volatiles compounds:

Total%w/wof carnosic acid and carnosolTotal%w/wof reference key volatiles15

Nevertheless, certain types of non-deodorised rosemary extracts, including rosemary essential oils or rosemary oleoresins, not standardised to antioxidant active compounds (carnosic acid (1) and carnosol (2)), are still used in the food industry for flavouring purposes only. It would not have made sense to include these types of extracts in the scope of the definition of the additive as the regulation aimed at covering antioxidant rosemary extracts only.

The European Union is not the only area where rosemary extracts are approved as food additives. In Japan, rosemary extracts are listed under number 365 in the List of Existing Additives and defined as “a substance composed mainly of carnosic acid, carnosol (2) and rosmanol (5) obtained from rosemary leaves or flowers”. Chinese food additive regulation GB2760-2011 approves the use of rosemary extracts under the Chinese numbering system CNS 04.017. Interestingly, it is a carnosic acid (1) derivative, carnosol (2) that is listed as the reference antioxidant compound in oil-soluble extracts. In most other countries, including the USA, rosemary extracts do not yet have any official status as technological additive.

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Diterpenes from rosemary (Rosmarinus officinalis): Defining their potential for anti-cancer activity

Sakina M. Petiwala, Jeremy J. Johnson, in Cancer Letters, 2015

Pharmacokinetics

Rosemary extract and its principal components, carnosic acid and carnosol, have been shown to be safe and well tolerated in animal studies; however, to better associate with human clinical trials, studies pertaining to pharmacokinetics and bioavailability of these compounds are a requisite. Three different pharmacokinetic studies have been reported describing the pharmacokinetic properties of carnosic acid, all within the rat species, in an attempt to establish the translational potential of carnosic acid as a pharmacological agent. In male Sprague-Dawley rats (190–220 g) carnosic acid was administered intragastrically (90 mg/kg) [68]. Oral administration of carnosic acid had the following parameters: time of maximum concentration (Tmax) (125.6 min), maximum plasma concentration (Cmax) (126 µM), area under the curve (AUC0-t) (21755.3 mg/L/min), and oral bioavailability (65.09%). A second study with male Sprague-Dawley rats (200–330 g) administered carnosic acid intragastrically (64.3 mg/kg) achieving the following pharmacokinetic parameters: Tmax (136.6 min), Cmax (105 µM), AUC0-t (7.05 mg/mL/min), and oral bioavailability (40.1%) [69]. A third pharmacokinetic evaluation was performed using a rosemary extract standardized to 40% carnosic acid [70]. Female Zucker rats (174.8 g ± 11.3) were administered 571 mg/kg of rosemary extract (containing 230 mg/kg of carnosic acid). A total of 26 diterpenes with the primary metabolites were identified with the most abundant being carnosic acid, carnosic acid 12-methyl ether, rosmariquinone, carnosic acid glucuronide, carnosol, and carnosol glucuronide. The Tmax of carnosic acid was 24 min with a Cmax of 26.6 µM and AUCall of 17.8 µM h. This study also determined the pharmacokinetic properties for carnosol that was a metabolic conversion from carnosic acid. The Tmax of carnosol was 13.3 min with a Cmax of 18.2 µM and AUCall of 137.4 µM h [70].

There appears to be some differences in the pharmacokinetic profile of pure carnosic acid versus carnosic acid from a standardized rosemary extract, specifically the Tmax and the Cmax. The maximum concentration of carnosic acid was 105–126 µM, while rosemary extract with ~2.5–3.5 times the amount of carnosic acid achieved a Cmax of only 26.6 µM. Regardless, in all three studies, plasma levels were well within the range that elicits a pharmacological response in cell culture models. Performing a dose translation from animals to humans with the following parameters: animal dose, mass of animal, body surface area, Km factor (i.e. surface area to weight ratio), the human equivalent dose of pure carnosic acid could range from 630 mg to 875 mg of carnosic acid in a 60 kg adult [71,72]. This dose could easily be achieved in two capsules to achieve plasma levels that are significantly higher than a variety of other dietary phytochemicals that have been evaluated in animal models and clinical trials [73,74]. The other parameter that was different between rosemary extract and pure carnosic acid was the Tmax. Absorption of rosemary derived carnosic acid was faster compared to pure carnosic acid with Tmax decreasing from 2 to 0.4 h when administered as an extract. One possible explanation is that within the extract protein, carbohydrates and dietary fiber were present and may contribute to an overall lower Cmax and decrease in Tmax. Another consideration that cannot be ruled out is the potential of other phytochemicals in rosemary modulating the absorption or metabolism profile of carnosic acid. A third explanation could be the difference of vehicle in the different studies. A final consideration is the difference in animal model used. The rosemary extract study utilized female Zucker rats, while the pure carnosic acid studies utilized Sprague-Dawley males. One apparent advantage of rosemary diterpenes such as carnosic acid is the high bioavailability with estimates ranging from 40 to 65% which is significantly higher than other phytochemicals which could be as low as 1–5% [68,69,73,74]. Taken together, the pharmacokinetic profile of carnosic acid appears to be well within the concentrations that have been used to report a variety of pharmacological actions in different cell culture models.

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Food Microbiology • Functional Foods and Nutrition

Andrea del Pilar Sánchez-Camargo, Miguel Herrero, in Current Opinion in Food Science, 2017

Anti-cancer activity

The anticancer effects of rosemary extract and its major phenols have been widely studied in the last years and several interesting reviews have addressed this issue [1••,2••,14–16]. Studies employing in-vitro models of leukemia [17,18], breast [19,20], lung [21], liver [21,22], pancreas [23,24], prostate [21,25,26], colon [27–30], cervical [31] and ovary [32] cancer cell lines have recently been carried out. Anticancer activity of rosemary extracts can be classified according to its ability to protect against the main three stages of cancer development: initiation (chemopreventive activity), promotion (anti-proliferative activity) and progression (anti-invasive or anti-metastatic activity). The chemopreventive activity of rosemary extracts has been related to its antioxidant properties, in particular with its capacity to scavenge free radicals, which can protect against ROS-induced oxidative damage to lipid, proteins, and DNA [1••,2••,33]. Besides to the protective effects derived from the response to oxidative stress, there are also several studies suggesting that CA and CS may exert an anti-proliferative activity [34]. For instance, a recent study performed on HepG2 liver cancer cells showed that CA possessed anti-proliferative activity mainly caused by its capacity to destabilize the mitochondrial membrane which leads the subsequent release of pro-apoptotic proteins into the cytoplasm. Once into the cytoplasm, those proteins are able to activate other proteins, such as caspase-3, which can promote programmed cell death. Furthermore, CA reduced the phosphorylation of Akt, which was partially inhibited by insulin, an activator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway [7]. This last signaling pathway is involved in the proliferation, growing and survival processes of cancer cells, and its inactivation can provoke cell death by apoptosis. Those results have also been corroborated in another study with the same cell line (HepG2) [8]. In spite of this, there is no a particular or universal signaling pathway consistently followed by the main polyphenols present in rosemary extracts for the killing of different types of cancer cells. Indeed, CA may induce apoptosis, cell cycle arrest, autophagy, and inhibition of cellular proliferation on various types of carcinomas. Recently, Bahri et al. have carried out an interesting summary of different molecular pathways involved in the anti-proliferative effect of CA in several types on cancer, including the dose and the specific effect of this compound on target cancer cells [1••]. The antimetastatic activity of rosemary extracts also has been deeply studied; metastasis is a complex process by which cancer cells are able to move from the original site of the tumor and to form tumors in other tissues. In order to invade, epithelial cancer cells need to penetrate through the basement membrane and to disorganize the extracellular matrix (ECM) [35]. In this context, proteases play an important role since they can either degrade or process the ECM components and thereby support cancer cell invasion. Some proteins such as the matrix metalloproteinase (MMP-2 and MMP-9) and the urokinase plasminogen activator (uPA) are responsible for the degradation of several ECM components and play important roles in the process of human colon cancer invasion and metastasis. In this regard, it has been demonstrated that CA is able to reduce the invasive capacity in Caco-2 colon cancer cell model by a reduction of MMP-2, MMP-9 and uPA [35]. Moreover, the effects of CA on the metastatic characteristics of B16F10 melanoma cells have been evaluated revealing that CA suppressed the adhesion of B16F10 cells, as well as the secretion of MMP-9, uPA, tissue inhibitor of metalloproteinase (TIMP)-1, and vascular cell adhesion molecule (VCAM)-1 [36]. Regarding CS, other studies showed that this component can also inhibit the cellular adhesion of different cancer cell lines such colon, ovary and breast, having a dose-dependent effect [37].

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Dietary plants, gut microbiota, and obesity: Effects and mechanisms

Shi-Yu Cao, ... Hua-Bin Li, in Trends in Food Science & Technology, 2019

4.3.3 Other spices

Rosemary is an aromatic shrub belonging to the Lamiaceae family. Rosemary extract is rich in carnosic acid, which reduces body weight gain through increasing the abundance of Blautia coccoides and Prevotella, and decreasing the populations of Lactobacillus/Leuconostoc/Pediococccus (Romo-Vaquero et al., 2014). Cinnamon is a spice harvested from the inner bark of trees belonging to the genus Cinnamomum. Cinnamon bark extracts could reduce fat mass gain, adipose tissue inflammation, and the Peptococcus, accompanied with the upregulation of antimicrobial peptides and tight junction proteins in the gut of C57BL/6J mice fed with HFD for 8 weeks (Van et al., 2018).

Collectively, turmeric, chili, rosemary, and cinnamon showed anti-obesity effects, at least partly via regulation of gut microbiota. The metabolites from gut microbiota could reduce the gut mucosa permeability with elevated levels of tight junction proteins, and mitigate the gut inflammation with reduced levels of inflammatory factors, like NF-κB. Many spices could inhibit the growth of bacteria, and are worthy of further investigation to find more spices and their active components with anti-obesity activity through modulating gut microbiota.

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The protective role of plant biophenols in mechanisms of Alzheimer's disease

Syed H. Omar, ... Hassan K. Obied, in The Journal of Nutritional Biochemistry, 2017

5.1.3.2 Evidence from animal studies

In a scopolamine impaired memory model of 6-week-old rats, oral administration of rosemary extract (200 mg/kg) and rosmarinic acid (10 mg/kg) for 4 weeks inhibited AChE and stimulated BChE activities in the brain [220]. It is worth mentioning that rosmarinic acid was less effective than the rosemary extract. A single oral administration of EGCG (100 mg/kg) to adult rats enhanced the extent and the duration of AChE inhibition by huperzine A. This synergistic effect is most likely due to improved huperzine transport [221]. The AChE inhibitory activity of quercetin was demonstrated in vivo using streptozotocin-treated mice, improving cerebral blood flow along with preventing memory impairment, oxidative stress, altered brain energy metabolism and cholinergic dysfunction [222]. Moreover, quercetin improved cognitive ability of mice and exhibited neuroprotective activity via inhibiting AChE [219].

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Food Microbiology • Functional Foods and Nutrition

Rashin Sedighi, ... Shengmin Sang, in Current Opinion in Food Science, 2015

In vitro studies

Studies were carried out in cell cultures and in vitro enzyme activity assays for addressing the potential anti-obesity action of RE or its major components (Table 2). Takahashi et al. [32] found that CA (IC50 = 0.86 μM) and carnosol inhibited the differentiation in mouse preadipocytes (3T3-L1 cells) into adipocytes, not other rosemary compounds such as luteolin, genkwanin, verbenone, rosmarinic acid, or caffeic acid. Through various in vitro assays, Takahashi et al. found evidence for a proposed mechanism for the inhibition of the adipocyte differentiation. Introduction of CA to 3T3-L1 cells interrupts the binding of Keap1 to Nrf2 leading to a nuclear translocation of Nrf2 and activated the Antioxidant Response Element (ARE), a known target of Nrf2. They also witnessed an increase in GSH metabolism and induction of a group of enzymes associated with ARE known as Phase 2. In contrast to the anti-differentiation effects seen by Takahashi et al., RE exhibited lipogenic activity in 3T3-L1 cells [32]. The apparent contradiction of these studies requires more study.

Table 2. In vivo and in vitro studies showing the effects of rosemary on obesity.

Year References Rosemary preparation Dosage/administration route Animal model Ex. duration Outcomes Conclusion
2004 Carnosic acid, a new class of lipid absorption inhibitor from sage [30]. Carnosic acid Oral, 20 mg/kg BW High fat (olive oil)-fed male ddY mice 14 d - BW reduced by ∼7%
- Serum TG: No difference for 14days, but reduced at 2, 4, 6 h after administration
- Increased weight of Epidydimal fat pad.
- Inhibited pancreatic lipase activity.
Inhibited pancreatic lipase activity.

2007 Adverse effects of rosemary (Rosmarinus officinalis L.) on reproductive function in adult male rats [36]. Rosemary 70% ethanol extract As drinking water at 250 and 500 mg/kg BW Male Sprague-Dawley rats 63 d - Body weight: No difference
- Serum TG: No difference
- Serum cholesterol: No difference
- Serum glucose: No difference
- No difference in ALT and AST

2009 Carnosic acid (CA) and carnosol (CS) inhibit adipocyte differentiation in mouse 3T3-L1 cells through induction of phase2 enzymes and activation of glutathione metabolism [32]. 3 μM CA, 3 μM CS CA stimulated GSH metabolism through induction of phase2 enzymes.
CA and CS increased intracellular GSH by activating ARE.
Inhibition adipocyte differentiation by CA in in vitro.

2010 Antidiabetic screening of commercial botanical products in 3T3-L1 adipocytes and db/db mice [37]. RE 50 μg/mL Increased lipogenesis.

2010 Inhibition of hormone sensitive lipase and pancreatic lipase by Rosmarinus officinalis extract and selected phenolic constituents [33]. IC50 of RE for PL 13.8 μg/mL, for HSL 95.2 μg/mL
IC50 of RA for PL 125.2 μg/mL, for HSL 51.5 μg/mL
Chlorogenic acid 96.5 and 21.3 μg/ML, Caffeic acid 32.6 and 40.1 μg/ML, Gallic acid 10.1 and 14.5 μg/ML
. - Inhibition of HSL and PL activities

2010 Rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and liver steatosis in mice fed a high-fat diet [26]. RE (contains 4% rosmarinic acid, 2.5% carnosic acid, and 5.6% carnosol) Oral, 20 mg/kg BW and 200 mg/kg BW (0.25% and 0.025% W/W diet) HFD fed male C57BL/6J mice 50 d - Body weight: Reduced by ∼11% with 200 mg/kg dose
- Liver TG: Reduced with 200 mg/kg
- Serum TG: No difference
- Serum cholesterol: No difference
- RE induced a higher fecal fat excretion
The results suggest that RE induced a higher fecal fat excretion, inhibited pancreatic lipase activity in vitro.

2011 Carnosic acid prevents obesity and hepatic steatosis in ob/ob mice [31]. Carnosic acid Oral, 0.05% (w/w) Male obese leptin-deficient (ob/ob) mice 5 wk - Body weight: Decreased
- Serum TG: Reduced by ∼60%
- Serum cholesterol: Reduced by ∼24%
- Liver TG: N.D.
- Serum glucose: Reduced by ∼18%
- Serum insulin: Decreased by 47%
- No difference in food intake.
- Plasma FFA decreased.
- CA improved the glucose tolerance in IPGTT.
CA inhibited adipocyte hypertrophy of WAT by a decrease of adipocyte size.

2011 Carnosic acid-rich rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and improves cholesterol levels and glycaemia in mice on a high-fat diet [27]. RE (20% carnosic acid) Oral, 500 mg/kg BW HFD fed male C57BL/6J mice 16 wk - Body weight: Decreased
- Serum TG: No difference
- Serum cholesterol: Reduced
- Serum glucose: Decreased
- Serum insulin: No difference
- RE increased fecal total lipid excretion and fecal energy excretion, and increased pancreatic lipase activity.
The results suggest that RE induced a higher fecal fat excretion by increasing the pancreatic lipase activity.

2012 Abietane diterpenoids of Rosmarinus officinalis and their diacylglycerol acyltransferase-inhibitory activity [34]. CS 62.5 ± 2.1 μM
Rosmanol 142.6 ± 1.9 μM
Rosmadial 144.2 ± 3.1 μM
12-O-methyl carnosic acid 85.2 ± 2.5 μM
Inhibited DGAT1 activity in vitro.
CS inhibited de novo intracellular triacylglycerol synthesis in human hepatocyte HepG2 cells.

2012 Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway [35]. CA 20 μM Reduced lipid accumulation in HepG2 cells.
Stimulated the phosphyorylation of both MAPK and EGFR in a time-dependent manner.
Reduced the expression level and activity of PPARγ.
Prevented lipid accumulation due to CA-induced PPARγ reduction and through the EGFR/MAPK pathway.

2012 Inhibition of gastric lipase as a mechanism for body weight and plasma lipids reduction in Zucker rats fed a rosemary extract rich in carnosic acid [8]. RE (40% carnosic acid) Oral, 0.5% (w/w) (RE 350–700 mg/kg; CA, 140–280 mg/kg) Female Zucker lean (fa/+) and obese (fa/fa) rats 64 d - Body weight: Reduced by 15%
- Serum TG: Decreased in lean rats, but no difference in obese rats
- Serum cholesterol: Decreased in lean rats, but no difference in obese rats
- Liver TG: No difference
-Serum glucose: No difference
- Serum insulin: Only reduced in lean rats.
- RE increased fecal weight.
- RE significantly inhibited gastric lipase activity in the stomach.
RE significantly inhibited gastric lipase activity in the stomach, which may cause a moderate reduction of fat absorption.

2012 The effect of rosemary (Rosmarinus officinalis L.) plant extracts on the immune response and lipid profile in mice [38]. RE (water soluble extract) Oral, 100 mg/kg BW d High cholesterol diet fed female BALB/c mice 15 d - Serum TG: Reduced
- Serum cholesterol: Reduced
- LDL decreased and HDL significantly increased by RE supplement.
Hypolipidemic activity of RE.

2012 Effects of rosemary on lipid profile in diabetic rats [39]. RE hot water extract Oral, 550 mg/mouse/day STZ-induced male albino rats 4 wk - Serum TG: Decreased by 24%
- Serum cholesterol: Decreased by 22%.
- Serum glucose: Decreased by20%LDL decreased by 27% and HDL increased by 18%.

2013 Rosemary (Rosmarinus officinalis L.) extract regulates glucose and lipid metabolism by activating AMPK and PPAR pathways in HepG2 cells [47••]. RE 2, 10 and 50 μg/mL . Activated AMPK pathway.
Transcriptionally regulated the genes involved in metabolism.
PPARγ inhibitor GW9662 diminished the effects of RE on glucose consumption.
RE reduced glycogen content and increased glycolysis
Activated the AMPK-ACC pathway.
Regulated genes including SIRT1, PGC1α, G6Pase, ACC, LDLR.
Increased the ECAR value with a dose-dependent manner.

2013 Phenolic compounds from rosemary (Rosmarinus officinalis L.) attenuate oxidative stress and reduce blood cholesterol concentrations in diet-induced hypercholesterolemic rats [29]. Rosemary aqueous extract (AQ, contain 1.87% Rosmarinic acid) and non-esterified phenolic fraction (NEPF, contain 5.71% carnosic acid) AQ 70 and 140 mg/kg BW, NEPF 7 and 14 mg/kg BW Hypercholesterolemic diet fed male Wistar rats 4 wk - Body weight: No difference
- Serum TG: No difference
- Serum cholesterol: Only decreased in 70 mg AQ/kg dose.
- On difference in food intake.
- 70 mg AQ/kg dose decreased non-HDL-cholesterol.
Cholesterol reduction may be attributed to a decrease in the micellar solubilization of cholesterol in the digestive tract, to an increase in bile flow, bile cholesterol and bile acid concentration and to a subsequent increase in the fecal excretion of steroids.

Bustanji et al. [33] found in vitro inhibitory effects of RE and its constituents (rosmarinic acid, chlorogenic acid, caffeic acid, and gallic acid) on both pancreatic lipase (PL) and hormone sensitive lipase (HSL) in a dose dependent manner. These data suggests that RE prevents digestion of dietary fat using a similar mechanism to that of Orlistat. The IC50 of RE for PL and HSL was 13.8 μg/mL and 95.2 μg/mL respectively. However, this in vitro relationship still needs confirmation in vivo.

Compounds from rosemary also have the potential to inhibit the formation of triglycerides by inhibiting diacylglycerol acyltransferase (DGAT). Cui et al. [34] found that eight abietane-type diterpenes isolated from rosemary exhibited in vitro DGAT inhibitory activity. Additionally, carnosol exhibited an inhibition of de novo intracellular triacylglycerol synthesis in HepG2 cells.

Wang et al. [35] reported that CA reduced lipid accumulation in HepG2 cells which is associated with EGFR and MAPK signaling. In contrast to the Takahashi's conclusions regarding the Nrf2 pathway they found that CA down-regulated both the expression level and activity of PPARγ through EGFR/MAPK signaling in HepG2 cells, and concluded that EGFR/MAPK signaling plays an important role in the inhibitory effects of CA on hepatocyte lipid accumulation. This cell culture in vitro study confirmed the effects of CA on lipid accumulation in liver in vivo. This result concurs with results of Ibarra et al. [27] who found that RE supplement inhibited pancreatic lipase activity and activated PPAR-γ in vitro.

Though we have many clues as to the anti-obesity mechanism of rosemary or CA, clarification requires further investigation.

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