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1.  Discovery and functional characterization of two diterpene synthases for sclareol biosynthesis in Salvia sclarea (L.) and their relevance for perfume manufacture 
BMC Plant Biology  2012;12:119.
Sclareol is a diterpene natural product of high value for the fragrance industry. Its labdane carbon skeleton and its two hydroxyl groups also make it a valued starting material for semisynthesis of numerous commercial substances, including production of Ambrox® and related ambergris substitutes used in the formulation of high end perfumes. Most of the commercially-produced sclareol is derived from cultivated clary sage (Salvia sclarea) and extraction of the plant material. In clary sage, sclareol mainly accumulates in essential oil-producing trichomes that densely cover flower calices. Manool also is a minor diterpene of this species and the main diterpene of related Salvia species.
Based on previous general knowledge of diterpene biosynthesis in angiosperms, and based on mining of our recently published transcriptome database obtained by deep 454-sequencing of cDNA from clary sage calices, we cloned and functionally characterized two new diterpene synthase (diTPS) enzymes for the complete biosynthesis of sclareol in clary sage. A class II diTPS (SsLPPS) produced labda-13-en-8-ol diphosphate as major product from geranylgeranyl diphosphate (GGPP) with some minor quantities of its non-hydroxylated analogue, (9 S, 10 S)-copalyl diphosphate. A class I diTPS (SsSS) then transformed these intermediates into sclareol and manool, respectively. The production of sclareol was reconstructed in vitro by combining the two recombinant diTPS enzymes with the GGPP starting substrate and in vivo by co-expression of the two proteins in yeast (Saccharomyces cerevisiae). Tobacco-based transient expression assays of green fluorescent protein-fusion constructs revealed that both enzymes possess an N-terminal signal sequence that actively targets SsLPPS and SsSS to the chloroplast, a major site of GGPP and diterpene production in plants.
SsLPPS and SsSS are two monofunctional diTPSs which, together, produce the diterpenoid specialized metabolite sclareol in a two-step process. They represent two of the first characterized hydroxylating diTPSs in angiosperms and generate the dihydroxylated labdane sclareol without requirement for additional enzymatic oxidation by activities such as cytochrome P450 monoxygenases. Yeast-based production of sclareol by co-expresssion of SsLPPS and SsSS was efficient enough to warrant the development and use of such technology for the biotechnological production of scareol and other oxygenated diterpenes.
PMCID: PMC3520730  PMID: 22834731
Diterpene; Sage; Salvia sclarea; Sclareol; Terpene synthase
2.  Randomized Controlled Trial for Salvia sclarea or Lavandula angustifolia: Differential Effects on Blood Pressure in Female Patients with Urinary Incontinence Undergoing Urodynamic Examination 
The aim of this study was to investigate the effect of inhalation of Salvia sclarea (clary sage; clary) or Lavandula angustifolia (lavender) essential oil vapors on autonomic nervous system activity in female patients with urinary incontinence undergoing urodynamic assessment.
Study design, location, and subjects
This study was a double-blind, randomized, controlled trial carried out in 34 female patients with urinary incontinence.
Outcome measure
The subjects were randomized to inhale lavender, clary, or almond (control) oil at concentrations of 5% (vol/vol) each. Systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and salivary cortisol were measured before and after inhalation of these odors for 60 minutes.
The clary oil group experienced a significant decrease in systolic blood pressure compared with the control (p=0.048) and lavender oil (p=0.026) groups, a significant decrease in diastolic blood pressure compared with the lavender oil group (p=0.034) and a significant decrease in respiratory rate compared with the control group (p<0.001). In contrast, the lavender oil group tended to increase systolic and diastolic blood pressure compared with the control group. Compared with the control group, inhalation of lavender oil (p=0.045) and clary oil (p<0.001) resulted in statistically significant reductions in respiratory rate.
These results suggest that lavender oil inhalation may be inappropriate in lowering stress during urodynamic examinations, despite its antistress effects, while clary oil inhalation may be useful in inducing relaxation in female urinary incontinence patients undergoing urodynamic assessments.
PMCID: PMC3700459  PMID: 23360656
3.  In Vitro Antibacterial and Antibiotic Resistance Modifying Effect of Bioactive Plant Extracts on Methicillin-Resistant Staphylococcus epidermidis 
The crude extracts of plants from Asteraceae and Lamiaceae family and essential oils from Salvia officinalis and Salvia sclarea were studied for their antibacterial as well as antibiotic resistance modifying activity. Using disc diffusion and broth microdilution assays we determined higher antibacterial effect of three Salvia spp. and by evaluating the leakage of 260 nm absorbing material we detected effect of extracts and, namely, of essential oils on the disruption of cytoplasmic membrane. The evaluation of in vitro interactions between plant extracts and oxacillin described in terms of fractional inhibitory concentration (FIC) indices revealed synergistic or additive effects of plant extracts and clearly synergistic effects of essential oil from Salvia officinalis with oxacillin in methicillin-resistant Staphylococcus epidermidis.
PMCID: PMC3810435  PMID: 24222768
4.  Cytotoxic, Antioxidant and Antimicrobial Activities and Phenolic Contents of Eleven Salvia Species from Iran  
The plants of the genus Salvia synthesize several types of secondary metabolites with antimicrobial, cytotoxic, and radical scavenging activities and are used in the folk medicine of different countries. Eleven Salvia species including S. aegyptiaca, S. aethiopis, S. atropatana, S. eremophila, S. hypoleuca, S. limbata, S. nemorosa, S. santolinifolia, S. sclarea, S. syriaca, and S. xanthocheila were collected from different localities in Iran and screened for their cytotoxic activity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. The antioxidant potential and total phenol contents of the plant extracts were assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and Folin- Ciocalteu reagent respectively and finally antimicrobial activity of the above extracts were determined by using agar disc diffusion (ADD) and nutrient broth micro-dilution (NBMD) bioassays. Cytotoxic activity of methanol, 80% methanol and dichloromethane extracts of these plants were assessed on 3 human cancer cell lines. All of the extracts of S. eremophila and S. santolinifolia were active at IC50 values of 10.5-75.2 μg extract/mL, while the methanol and dichloromethane extracts of S. limbata, S. hypoleuca and S. aethiopis showed considerable cytotoxic activity against the tested cell lines. Among the tested plants for their antioxidant activity, S. nemorosa, S. atropatana, S. santolinifolia, and S. eremophila were the most active radical scavengers with higher total phenol contents while, S. limbata, S. xanthocheila and S. aegyptiaca were the weakest ones. The methanol extracts of S. santolinifolia, S. eremophila, S. sclarea and S. limbata inhibited the growth of all tested bacterial strains.
PMCID: PMC3920696  PMID: 24523760
Salvia; Phenolics; DPPH; Radical-scavenging; Cytotoxic activity; Antibacterial activity
5.  Labdane-Type Diterpene and Two Flavones from Salvia Sharifii Rech. f. and Esfan. and their Biological Activities 
Two flavones, ladanein and 6-hydroxy-5,7,4′-trimethoxyflavone and one labdane-type diterpene, ent-13-epi-manoyloxide, were isolated from an ethyl acetate-methanol extract of the aerial parts of Salvia sharifii. The compounds were purified using several chromatographic methods. Structural elucidation of the compounds was performed using their 1H and 13C-NMR data, EI mass and UV spectral data. The compounds have been subjected to antimicrobial, antioxidant and cytotoxic activity. The diterpene showed higher cytotoxic activity than the flavones while the later compounds were better antioxidants compared with the isolated diterpene.
PMCID: PMC3813239  PMID: 24250614
TLadanein; 6-hydroxy-5; 7; 4′-trimethoxyflavone; Ent-13-epi-manoyloxide; Antioxidant; Antimicrobial; Cytotoxic
6.  Presence of monoterpene synthase in four Labiatae species and Solid-Phase Microextraction- Gas chromatography-Mass Spectroscopy analysis of their aroma profiles 
Pharmacognosy Research  2014;6(2):138-142.
The family Lamiaceae (Labiatae) has included some medicinal plants. some monoterpene synthases, including linalool and limonene synthases, have been cloned and functionally characterized from several plants of Labiatae family.
Materials and Methods:
In this study, presence of linalool and limonene synthases, in four species of Labiatae family including Nepeta cataria, Lavandula angustifolia, Hyssopus officinalis and Salvia sclarea has been determined by molecular biological techniques together with the Head space SPME – GC-MS analysis of the aroma profile of these species.
Indicated that none of the plant species produced distinguishable bands with primer pairs related to d-limonene synthase. Distinguishable bands around 1800 bp in cDNA samples of L. angustifolia, H. officinalis and S. sclarea were observed regarding to the presence of linalool synthase. Head space SPME-GC-MS analysis of the aroma profiles of the above-mentioned plants showed that linalool (31.0%), linalyl acetate (18.2%), were found as the major compounds of L. angustifolia, while geraniol (5.5%), nerol (34.0%) and α- citral (52.0%) were identified as the main compounds of the N. cataria. The major components of H. officinalis and S. sclarea oils were determined as cis-pinocamphone (57.3%), and linalool (19.0%), linalyl acetate (51.5%), respectively.
H. officinalis was rich of cyclic monoterpenes, L. angustifolia, N. cataria and S. sclarea showed considerable amount of linear monoterpenes. The aroma profile of the above-mentioned plants contained low concentration of sesquiterpenes except N. cataria, which indicated no sesquiterpene. The profiles of the main components of these plants are in agreement with molecular assays.
PMCID: PMC3996750  PMID: 24761118
Essential oil; headspace solid phase microextraction; labiatae; monoterpene synthase
7.  In vitro assay for the anti-brucella activity of medicinal plants against tetracycline-resistant Brucella melitensis *  
Brucellosis, a zoonosis caused by four species of brucella, has a high morbidity. Brucella melitensis is the main causative agent of brucellosis in both human and small ruminants. As an alternative to conventional antibiotics, medicinal plants are valuable resources for new agents against antibiotic-resistant strains. The aim of this study was to investigate the usage of native plants for brucellosis treatment. For this purpose, the anti-brucella activities of ethanolic and methanolic extracts of Salvia sclarea, Oliveria decumbens, Ferulago angulata, Vitex pseudo-negundo, Teucrium polium, Plantago ovata, Cordia myxa, and Crocus sativus were assessed. The activity against a resistant Br. melitensis strain was determined by disc diffusion method at various concentrations from 50–400 mg/ml. Antibiotic discs were also used as a control. Among the evaluated herbs, six plant (Salvia sclarea, Oliveria decumbens, Ferulago angulata, Vitex pseudo-negundo, Teucrium polium, and Crocus sativus) showed anti-brucella activity. Oliveria decumbens was chosen as the most effective plant for further studies. A tested isolate exhibited resistance to tetracycline, nafcillin, oxacillin, methicillin, and colistin. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values for Oliveria decumbens against resistant Br. melitensis were the same (5 mg/ml), and for gentamicin they were both 2 mg/ml. Time-kill kinetics for a methanolic extract of Oliveria decumbens was 7 h whereas for an ethanolic extract it was 28 h. Also, Oliveria decumbens extracts showed a synergistic effect in combination with doxycycline and tetracycline. In general, the similar values of MIC and MBC for Oliveria decumbens suggest that these extracts could act as bactericidal agents against Br. melitensis. In addition to Oliveria decumbens, Crocus sativus and Salvia sclarea also had good anti-brucella activity and these should be considered for further study.
PMCID: PMC2897020  PMID: 20593515
Brucellosis; Antibiotic resistance; Brucella melitensis; Medicinal plant; Oliveria decumbens
8.  Aqueous extracts from peppermint, sage and lemon balm leaves display potent anti-HIV-1 activity by increasing the virion density 
Retrovirology  2008;5:27.
Aqueous extracts from leaves of well known species of the Lamiaceae family were examined for their potency to inhibit infection by human immunodeficiency virus type 1 (HIV-1).
Extracts from lemon balm (Melissa officinalis L.), peppermint (Mentha × piperita L.), and sage (Salvia officinalis L.) exhibited a high and concentration-dependent activity against the infection of HIV-1 in T-cell lines, primary macrophages, and in ex vivo tonsil histocultures with 50% inhibitory concentrations as low as 0.004%. The aqueous Lamiaceae extracts did not or only at very high concentrations interfere with cell viability. Mechanistically, extract exposure of free virions potently and rapidly inhibited infection, while exposure of surface-bound virions or target cells alone had virtually no antiviral effect. In line with this observation, a virion-fusion assay demonstrated that HIV-1 entry was drastically impaired following treatment of particles with Lamiaceae extracts, and the magnitude of this effect at the early stage of infection correlated with the inhibitory potency on HIV-1 replication. Extracts were active against virions carrying diverse envelopes (X4 and R5 HIV-1, vesicular stomatitis virus, ecotropic murine leukemia virus), but not against a non-enveloped adenovirus. Following exposure to Lamiaceae extracts, the stability of virions as well as virion-associated levels of envelope glycoprotein and processed Gag protein were unaffected, while, surprisingly, sucrose-density equilibrium gradient analyses disclosed a marked increase of virion density.
Aqueous extracts from Lamiaceae can drastically and rapidly reduce the infectivity of HIV-1 virions at non-cytotoxic concentrations. An extract-induced enhancement of the virion's density prior to its surface engagement appears to be the most likely mode of action. By harbouring also a strong activity against herpes simplex virus type 2, these extracts may provide a basis for the development of novel virucidal topical microbicides.
PMCID: PMC2288616  PMID: 18355409
9.  Genus Cistus: a model for exploring labdane-type diterpenes' biosynthesis and a natural source of high value products with biological, aromatic, and pharmacological properties 
The family Cistaceae (Angiosperm, Malvales) consists of 8 genera and 180 species, with 5 genera native to the Mediterranean area (Cistus, Fumara, Halimium, Helianthemum, and Tuberaria). Traditionally, a number of Cistus species have been used in Mediterranean folk medicine as herbal tea infusions for healing digestive problems and colds, as extracts for the treatment of diseases, and as fragrances. The resin, ladano, secreted by the glandular trichomes of certain Cistus species contains a number of phytochemicals with antioxidant, antibacterial, antifungal, and anticancer properties. Furthermore, total leaf aqueous extracts possess anti-influenza virus activity. All these properties have been attributed to phytochemicals such as terpenoids, including diterpenes, labdane-type diterpenes and clerodanes, phenylpropanoids, including flavonoids and ellagitannins, several groups of alkaloids and other types of secondary metabolites. In the past 20 years, research on Cistus involved chemical, biological and phylogenetic analyses but recent investigations have involved genomic and molecular approaches. Our lab is exploring the biosynthetic machinery that generates terpenoids and phenylpropanoids, with a goal to harness their numerous properties that have applications in the pharmaceutical, chemical and aromatic industries. This review focuses on the systematics, botanical characteristics, geographic distribution, chemical analyses, biological function and biosynthesis of major compounds, as well as genomic analyses and biotechnological approaches of the main Cistus species found in the Mediterranean basin, namely C. albidus, C. creticus, C. crispus, C. parviflorus, C. monspeliensis, C. populifolius, C. salviifolius, C. ladanifer, C. laurifolius, and C. clusii.
PMCID: PMC4052220  PMID: 24967222
Cistus; biosynthesis; labdane-type diterpenes; phenylpropanoids; biological action; genomic approaches
10.  Cancer cell spheroids as a model to evaluate chemotherapy protocols 
Cancer Biology & Therapy  2012;13(12):1205-1213.
To determine whether the spheroid culture can be used to evaluate drug efficacy, we have evaluated the toxicity of free or carrier-associated doxorubicin as a single drug or in combination with other antineoplastic agents using the spheroid cultures of drug-resistant cancer cells. Paclitaxel, cisplatin, dexamethasone, mitoxantrone, sclareol or methotrexate were used in combination with doxorubicin. The effect of the treatment protocols on free, micellar and liposomal doxorubicin accumulation in spheroids and on resulting toxicity was evaluated by fluorescence and lactate dehydrogenase release, respectively. Enhanced doxorubicin accumulation and toxicity were observed after spheroid pretreatment with mitoxantrone or paclitaxel. Effects of the drug combination with doxorubicin were sequence dependent, use of doxorubicin as the first drug being the least inducer of toxicity. Finally, spheroids were recognized by a cancer cell-specific antibody. Our results suggest the usefulness of spheroids to evaluate chemotherapy combinations.
PMCID: PMC3469478  PMID: 22892843
cancer cell spheroids; doxorubicin; paclitaxel; mitoxantrone; combination
11.  Inhibition of HIV-1 infection by aqueous extracts of Prunella vulgaris L. 
Virology Journal  2011;8:188.
The mint family (Lamiaceae) produces a wide variety of constituents with medicinal properties. Several family members have been reported to have antiviral activity, including lemon balm (Melissa officinalis L.), sage (Salvia spp.), peppermint (Mentha × piperita L.), hyssop (Hyssopus officinalis L.), basil (Ocimum spp.) and self-heal (Prunella vulgaris L.). To further characterize the anti-lentiviral activities of Prunella vulgaris, water and ethanol extracts were tested for their ability to inhibit HIV-1 infection.
Aqueous extracts contained more anti-viral activity than did ethanol extracts, displaying potent antiviral activity against HIV-1 at sub μg/mL concentrations with little to no cellular cytotoxicity at concentrations more than 100-fold higher. Time-of-addition studies demonstrated that aqueous extracts were effective when added during the first five hours following initiation of infection, suggesting that the botanical constituents were targeting entry events. Further analysis revealed that extracts inhibited both virus/cell interactions and post-binding events. While only 40% inhibition was maximally achieved in our virus/cell interaction studies, extract effectively blocked post-binding events at concentrations similar to those that blocked infection, suggesting that it was targeting of these latter steps that was most important for mediating inhibition of virus infectivity.
We demonstrate that aqueous P. vulgaris extracts inhibited HIV-1 infectivity. Our studies suggest that inhibition occurs primarily by interference of early, post-virion binding events. The ability of aqueous extracts to inhibit early events within the HIV life cycle suggests that these extracts, or purified constituents responsible for the antiviral activity, are promising microbicides and/or antivirals against HIV-1.
PMCID: PMC3096947  PMID: 21513560
human immunodeficiency virus; HIV; antiviral; microbicide; plant extract; self-heal
12.  Effects of Three Medicinal Plants Extracts in Experimental Diabetes: Antioxidant Enzymes Activities and Plasma Lipids Profiles inComparison with Metformin 
In the present study we aimed to evaluate the effects of methanolic extracts of the bulbs of Garlic (Allium sativum L., Alliaceae) and Persian shallot (Allium ascalonicum L., Alliaceae ) and leaves of Sage (Salvia officinalis L., Lamiaceae ), ASE, AAE and SOE respectively, on the antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) activities and on the levels of plasma lipids profiles such as triglycerides (TG), total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL) in Alloxan diabetic Wistar rats.
In comparison with diabetic control rats in diabetic treated rats, AAE increases the activities of SOD (65%), GPX (43%) and CAT (55%). ASE and SOE increase SOD activity by 60% and 33% respectively. ASE reduces TC (34%), SOE decreases TG (40%) and LDL (30%) and AAE reduces VLDL (24%). Metformin exhibits mild antioxidant and hypolipidemic properties. Results of quantitative phytochemical analysis show that the methanolic garlic and Persian shallot bulbs extracts contain secondary metabolites including alkaloids (3.490% and 3.430%), glycosides (18.023% and 13.301%) and saponins (0.812% and 0.752%). Methanolic sage leaves extract contains flavonoids (1.014%), glycosides (23.142%) and saponins (2.096%). The total phenolic contents of ASE, AAE and SOE were in order 4.273, 3.621 and 6.548 mg GAE/g dry weight (DW).
These results suggest that Allium sativum, Allium ascalonicum and Salvia officinalis are beneficial in the control of diabetes by noticeable antioxidant and hypolipidemic properties.
PMCID: PMC3813132  PMID: 24250517
Allium ascalonicum; Allium sativum; Salvia officinalis; Antioxidant enzymes; Plasma lipids
13.  Hypoglycemic Effects of Three Medicinal Plants in Experimental Diabetes: Inhibition of Rat Intestinal α-glucosidase and Enhanced Pancreatic Insulin and Cardiac Glut-4 mRNAs Expression 
Garlic (Allium sativum L., Alliaceae), Persian shallot (Allium ascalonicum L., Alliaceae ) and Sage (Salvia officinalis L., Lamiaceae) are believed to have hypoglycemic properties and have been used traditionally as antidiabetic herbal medicines in Iran. In this study, diabetes was induced by subcutaneous injection of alloxan monohydrate (100 mg kg−1) to male Wistar rats. Antidiabetic effects of methanolic extracts of the above mentioned three plants on alloxan-diabetic rats was investigated in comparison with the effects of antidiabetic drugs such as acarbose, glibenclamide and metformin by measuring postprandial blood glucose (PBG), oral glucose tolerance test (OGTT), inhibition of rat intestinal α-glucosidase enzymes activities and pancreatic Insulin and cardiac Glut-4 mRNAs expression. In short term period, hypoglycemic effects of A. sativum and A. ascalonicum showed significant reduction of PBG similar to glibenclamide (5 mg kg−1 bw) while S. officinalis significantly reduced PBG similar to acarbose (20 mg kg−1 bw). After 3 weeks of treatment by methanolic plant extracts, significant chronic decrease in the PBG was observed similar to metformin (100 mg kg−1 bw). For OGTT, S. officinalis reduced PBG in a similar way as acarbose (20 mg kg−1 bw). Intestinal sucrase and maltase activities were inhibited significantly by A. sativum, A. ascalonicum and S. officinalis. In addition, we observed increased expression of Insulin and Glut-4 genes in diabetic rats treated with these plants extracts. Up regulation of Insulin and Glut-4 genes expression and inhibition of α-glucosidaseactivities are the two mechanisms that play a considerable role in hypoglycemic action of garlic, shallot and sage.
PMCID: PMC3813273  PMID: 24250646
Diabetes; Glut-4; Insulin; OGTT; PBG
14.  Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial 
Phlebology  2012;27(2):67-72.
The purpose of this study was to assess the safety and efficacy of the ClariVein® system that employs mechanochemical ablation of the great saphenous vein (GSV).
Patients eligible for ablation of the GSV underwent micropuncture access with only local anaesthesia to insert a 4 or 5 Fr sheath. The ClariVein® catheter was placed through the sheath, the wire was extruded, and the distal tip of the wire positioned 2 cm from the saphenofemoral junction under ultrasound guidance. Catheter wire rotation was then activated for 2–3 seconds at approximately 3500 rpm. With the wire rotating, infusion of the sclerosant was started simultaneously with catheter pullback. The sclerosant used was 1.5% liquid sodium tetradecyl sulphate (Sotradecol©, Bioniche Pharma Group, Geneva, Switzerland).
Thirty GSVs in 29 patients were treated. All patients have reached six-month follow-up; the average number of postoperative days is 260. No adverse events have been reported. The Primary Closure Rate is 96.7%.
Mechanochemical ablation appears to be safe and efficacious. The ClariVein® technique eliminates the need for tumescent anaesthesia. The great majority of incompetent GSVs can be treated with this technique.
PMCID: PMC3277920  PMID: 21803800
chronic venous disease; endovenous techniques; ultrasound-guided sclerotherapy; varicose veins; venous insufficiency
15.  Antioxidant Capacity and Polyphenolic Composition as Quality Indicators for Aqueous Infusions of Salvia officinalis L. (sage tea) 
Sage (Salvia officinalis L.) is used as an herbal medicinal product, with the most typical form of application as infusion with boiling water (sage tea). The well-established traditional uses include symptomatic treatment of mild dyspeptic complaints, the treatment of inflammations in the mouth and the throat, and relief of excessive sweating and relief of minor skin inflammations. In this study, sage teas prepared from commercially available products were chemically analyzed for polyphenolic content using liquid chromatography, for antioxidant potential using the oxygen radical absorbance capacity method, and for the Folin–Ciocalteu (FC) index. The sage teas showed a high variation for all parameters studied (up to 20-fold differences for rosmarinic acid). Univariate and multivariate analyses showed that the antioxidant potential, which varied between 0.4 and 1.8 mmol trolox equivalents/100 mL, was highly dependent on rosmarinic acid and its derivatives. The FC index also showed a high correlation to these polyphenols, and could therefore be used as a screening parameter for sage tea quality. The considerable differences in polyphenolic composition and antioxidant capacity between the brands lead to a demand for quality standardization, especially if these sage teas are to be used for therapeutic purposes. Further research also appears to be necessary to characterize the dose–benefit relationship, as sage may also contain a constituent (thujone) with potentially adverse effects.
PMCID: PMC3242359  PMID: 22194722
Salvia officinalis L.; tea infusion; polyphenols; antioxidant capacity; ORAC
16.  Cardiovascular Activity of Labdane Diterpenes from Andrographis paniculata in Isolated Rat Hearts 
The dichloromethane (DCM) extract of Andrographis paniculata Nees was tested for cardiovascular activity. The extract significantly reduced coronary perfusion pressure by up to 24.5 ± 3.0 mm Hg at a 3 mg dose and also reduced heart rate by up to 49.5 ± 11.4 beats/minute at this dose. Five labdane diterpenes, 14-deoxy-12-hydroxyandrographolide (1), 14-deoxy-11,12-didehydroandrographolide (2), 14-deoxyandrographolide (3), andrographolide (4), and neoandrographolide (5), were isolated from the aerial parts of this medicinal plant. Bioassay-guided studies using animal model showed that compounds, (2) and (3) were responsible for the coronary vasodilatation. This study also showed that andrographolide (4), the major labdane diterpene in this plant, has minimal effects on the heart.
PMCID: PMC3321480  PMID: 22536026
17.  Deodorant effects of a sage extract stick: Antibacterial activity and sensory evaluation of axillary deodorancy 
Deodorant products prevent the growth and activity of the degrading apocrine gland bacteria living in the armpit. Common antibacterial agents in the market like triclosan and aluminum salts, in spite of their suitable antibacterial effects, increase the risk of Alzheimer's disease, breast and prostate cancers or induce contact dermatitis. Therefore, plant extracts possessing antibacterial effects are of interest. The aim of the present study was to verify the in vitro antimicrobial effects of different sage extracts against two major bacteria responsible for axillary odor, and to evaluate the deodorant effect of a silicon-based stick containing sage extracts in different densities in humans.
Materials and Methods:
Different fractions of methanolic extract of Salvia officinalis (sage) were evaluated on a culture of armpit skin surface of volunteers through agar microdilution antimicrobial assay. Then, randomized, double-blind placebo-controlled clinical trial with the best antibacterial fraction was conducted on 45 female healthy volunteers. Participants were treated with a single dose in four groups, each containing 15 individuals: Group 1 (200 μg/mL), 2 (400 μg/mL), 3 (600 μg/mL) of dichloromethane sage extract, and placebo (without extract). A standard sensory evaluation method for the evaluation of deodorant efficacy was used before, and two hours, four hours, and eight hours after single application of a deodorant or placebo (ASTM method E 1207-87 Standard Practice for the Sensory Evaluation of Axillary Deodorancy).
The data were analyzed with two factors relating to densities and time. In 45 participants with a mean [± standard deviation (SD)] age of 61.5±11.8 years, statistically significant within-group differences were observed before and two, four, and eight hours after deodorant treatment for groups 1, 2, and 3. Groups 1, 2, and 3 had a significantly smaller odor score than placebo after two, four, and eight hours (P < 0.001). In a comparison of different deodorant densities, the interaction effect was not significant between deodorant 200 and 400 μg/mL, but was significant between 200 and 600 and between 400 and 600 μg/mL sage extract sticks (P < 0.001). Before running the sensory evaluation of the deodorant sticks on the subjects, a rabbit skin patch test was used to demonstrate that the formulation had no irritants.
A single treatment with a stick deodorant containing dichloromethane sage extract of 200, 400, or 600 μg/mL concentrations was effective in reducing the axillary malodor level compared with the control, in healthy subjects.
PMCID: PMC3897065  PMID: 24497852
Antibacterial activity; axillary deodorant; sage extract; stick
18.  2012 David W. Robertson Award for Excellence in Medicinal Chemistry: Neoclerodanes as Atypical Opioid Receptor Ligands⊥ 
Journal of medicinal chemistry  2013;56(9):3435-3443.
The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling & Játiva (Lamiaceae). Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because (1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and (2) its effects are not mediated through the previously investigated targets of psychotomimetics. This perspective outlines our research program, illustrating a new direction to the development of tools to further elucidate the biological mechanisms of drug tolerance and dependence. The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other CNS disorders.
PMCID: PMC3671615  PMID: 23548164
Opioids; salvinorin A; Salvia divinorum; herkinorin; neoclerodanes
19.  (4R,5R,6S,7R,8S,9R,10S,13S)-7,8β-Epoxy­momilactone-A 
The title compound, C20H26O4, was extracted from Leucas Urticifolia, a wild Lamiaceae herb distributed in the Punjab, Baluchistan, Sindh and the Rajputana desert of Pakistan. The plant is utilized for various medicinal applications by the local community. The title compound is based on the pimarane–diterpene skeleton. The mol­ecule exhibits an ep­oxy ring fused to momilactone-A, leading to a penta­cyclic mol­ecular structure. The absolute configuration was assigned by comparison with the crystal structure of momilactone, but needs further verification. The crystal structure is governed by four inter­molecular hydrogen-bond inter­actions of the C—H⋯O type.
PMCID: PMC2961202  PMID: 21202375
20.  QCM-Arrays for Sensing Terpenes in Fresh and Dried Herbs via Bio-Mimetic MIP Layers † 
Sensors (Basel, Switzerland)  2010;10(7):6361-6376.
A piezoelectric 10 MHz multichannel quartz crystal microbalance (MQCM), coated with six molecularly imprinted polystyrene artificial recognition membranes have been developed for selective quantification of terpenes emanated from fresh and dried Lamiaceae family species, i.e., rosemary (Rosmarinus Officinalis L.), basil (Ocimum Basilicum) and sage (Salvia Officinalis). Optimal e-nose parameters, such as layer heights (1–6 KHz), sensitivity <20 ppm of analytes, selectivity at 50 ppm of terpenes, repeatability and reproducibility were thoroughly adjusted prior to online monitoring. Linearity in reversible responses over a wide concentration range <20–250 ppm has been achieved. Discrimination between molecules of similar molar masses, even for isomers, e.g. α-pinene and β-pinene is possible. The array has proven its sensitive and selective properties of sensor responses (20–1,200 Hz) for the difference of fresh and dried herbs. The sensor data attained was validated by GC-MS, to analyze the profiles of sensor emanation patterns. The shelf-life of herbs was monitored via emanation of organic volatiles during a few days. Such an array in association with data analysis tools can be utilized for characterizing complex mixtures.
PMCID: PMC3231110  PMID: 22163554
quartz crystal microbalance; chemical sensor; molecular imprinting; herbs; terpenes
21.  A novel dietary supplement containing multiple phytochemicals and vitamins elevates hepatorenal and cardiac antioxidant enzymes in the absence of significant serum chemistry and genomic changes 
A novel dietary supplement composed of three well-known phytochemicals, namely, Salvia officinalis (sage) extract, Camellia sinensis (oolong tea) extract, and Paullinia cupana (guarana) extract, and two prominent vitamins (thiamine and niacin) was designed to provide nutritional support by enhancing metabolism and maintaining healthy weight and energy. The present study evaluated the safety of this dietary supplement (STG; S, sage; T, tea; G, guarana) and assessed changes in target organ antioxidant enzymes (liver, kidneys and heart), serum chemistry profiles and organ histopathology in Fisher 344 rats. Adult male and female Fisher 344 rats were fed control (no STG) or STG containing (1X and 7X, 1X = daily human dose) diets and sacrificed after 2 and 4 months. Serum chemistry analysis and histopathological examination of three vital target organs disclosed no adverse influence on protein, lipid and carbohydrate profiles, genomic integrity of the liver and/or the tissue architecture. However, analysis of the most important antioxidant components in the liver, kidney and heart homogenates revealed a dramatic increase in total glutathione concentrations, glutathione peroxidase and superoxide dismutase enzyme activities. Concomitantly, oxidative stress levels (malondialdehyde accumulation) in these three organs were less than control. Organ specific serum markers (ALT/AST for the liver; CPK/AST/LDH for the heart; BUN/creatinine for kidneys) and the genomic integrity disclosed no STG-induced alteration. Some of the serum components (lipid and protein) showed insignificant changes. Overall, STG-exposed rats were more active, and the results suggest that STG exposure produces normal serum chemistry coupled with elevated antioxidant capacity in rats fed up to seven times the normal human dose and does not adversely influence any of the vital target organs. Additionally, this study reiterates the potential benefits of exposure to a pharmacologically relevant combination of phytochemicals compared to a single phytochemical entity.
PMCID: PMC2952097  PMID: 20716937
antioxidant enzymes; sage extract; oolong tea extract; guarana extract; oxidative stress; liver; kidney; heart; genomic integrity; Fisher 344 rats
22.  Compounds from the Fruits of the Popular European Medicinal Plant Vitex agnus-castus in Chemoprevention via NADP(H):Quinone Oxidoreductase Type 1 Induction 
As part of our continuing efforts in the search for potential biologically active compounds from medicinal plants, we have isolated 18 compounds including two novel nitrogen containing diterpenes from extracts of the fruits of Vitex agnus-castus. These isolates, along with our previously obtained novel compound vitexlactam A (1), were evaluated for potential biological effects, including cancer chemoprevention. Chemically, the nitrogenous isolates were found to be two labdane diterpene alkaloids, each containing an α, β-unsaturated γ-lactam moiety. Structurally, they were elucidated to be 9α-hydroxy-13(14)-labden-16,15-amide (2) and 6β-acetoxy-9α-hydroxy-13(14)-labden-15,16-amide (3), which were named vitexlactams B and C, respectively. The 15 known isolates were identified as vitexilactone (4), rotundifuran (5), 8-epi-manoyl oxide (6), vitetrifolin D (7), spathulenol (8), cis-dihydro-dehydro-diconiferylalcohol-9-O-β-D-glucoside (9), luteolin-7-O-glucoside (10), 5-hydroxy-3,6,7,4′-tetramethoxyflavone (11), casticin (12), artemetin (13), aucubin (14), agnuside (15), β-sitosterol (16), p-hydroxybenzoic acid (17), and p-hydroxybenzoic acid glucose ester (18). All compound structures were determined/identified on the basis of 1D and/or 2D NMR and mass spectrometry techniques. Compounds 6, 8, 9, and 18 were reported from a Vitex spieces for the first time. The cancer chemopreventive potentials of these isolates were evaluated for NADP(H):quinone oxidoreductase type 1 (QR1) induction activity. Compound 7 demonstrated promising QR1 induction effect, while the new compound vitexlactam (3) was only slightly active.
PMCID: PMC3638617  PMID: 23662135
23.  Effect of plant extracts on Alzheimer's disease: An insight into therapeutic avenues 
Alzheimer's disease (AD) is a devastative neurodegenerative disorder which needs adequate studies on effective treatment options. The extracts of plants and their effect on the amelioration of AD symptoms have been extensively studied. This paper summarizes the mechanisms like acetylcholinesterase (AChE) inhibition, modification of monoamines, antiamyloid aggregation effect, and antioxidant activity which are actively entailed in the process of amelioration of AD symptoms. These effects are induced by extracts of a few plants of different origin like Yizhi Jiannao, Moringa oleifera (Drumstick tree), Ginkgo Biloba (Ginkgo/Maidenhair tree), Cassia obtisufolia (Sicklepod), Desmodium gangeticum (Sal Leaved Desmodium), Melissa officinalis (Lemon Balm), and Salvia officinalis (Garden sage, common sage).
PMCID: PMC3122981  PMID: 21716802
Alzheimer's disease; antiamyloid aggregation; antioxidants; acetyl choline esterase inhibitors; plant extracts.
24.  Benzyl Isothiocyanate, a Major Component from the Roots of Salvadora Persica Is Highly Active against Gram-Negative Bacteria 
PLoS ONE  2011;6(8):e23045.
Plants produce a number of antimicrobial substances and the roots of the shrub Salvadora persica have been demonstrated to possess antimicrobial activity. Sticks from the roots of S. persica, Miswak sticks, have been used for centuries as a traditional method of cleaning teeth. Diverging reports on the chemical nature and antimicrobial repertoire of the chewing sticks from S. persica led us to explore its antibacterial properties against a panel of pathogenic or commensal bacteria and to identify the antibacterial component/s by methodical chemical characterization. S. persica root essential oil was prepared by steam distillation and solid-phase microextraction was used to sample volatiles released from fresh root. The active compound was identified by gas chromatography-mass spectrometry and antibacterial assays. The antibacterial compound was isolated using medium-pressure liquid chromatography. Transmission electron microscopy was used to visualize the effect on bacterial cells. The main antibacterial component of both S. persica root extracts and volatiles was benzyl isothiocyanate. Root extracts as well as commercial synthetic benzyl isothiocyanate exhibited rapid and strong bactericidal effect against oral pathogens involved in periodontal disease as well as against other Gram-negative bacteria, while Gram-positive bacteria mainly displayed growth inhibition or remained unaffected. The short exposure needed to obtain bactericidal effect implies that the chewing sticks and the essential oil may have a specific role in treatment of periodontal disease in reducing Gram-negative periodontal pathogens. Our results indicate the need for further investigation into the mechanism of the specific killing of Gram-negative bacteria by S. persica root stick extracts and its active component benzyl isothiocyanate.
PMCID: PMC3148225  PMID: 21829688
25.  High-level diterpene production by transient expression in Nicotiana benthamiana 
Plant Methods  2013;9:46.
Characterization of plant terpene synthases is typically done by production of recombinant enzymes in Escherichia coli. This is often difficult due to solubility and codon usage issues. Furthermore, plant terpene synthases which are targeted to the plastids, such as diterpene synthases, have to be shortened in a more or less empirical approach to improve expression. We report here an optimized Agrobacterium-mediated transient expression assay in Nicotiana benthamiana for plant diterpene synthase expression and product analysis.
Agrobacterium-mediated transient expression of plant diterpene synthases in N. benthamiana led to the accumulation of diterpenes within 3 days of infiltration and with a maximum at 5 days. Over 50% of the products were exported onto the leaf surface, thus considerably facilitating the analysis by reducing the complexity of the extracts. The robustness of the method was tested by expressing three different plant enzymes, cembratrien-ol synthase from Nicotiana sylvestris, casbene synthase from Ricinus communis and levopimaradiene synthase from Gingko biloba. Furthermore, co-expression of a 1-deoxy-D-xylulose-5-phosphate synthase from tomato and a geranylgeranyl diphosphate synthase from tobacco led to a 3.5-fold increase in the amount of cembratrien-ol produced, with maximum yields reaching 2500 ng/cm2.
With this optimized method for diterpene synthase expression and product analysis, a single infiltrated leaf of N. benthamiana would be sufficient to produce quantities required for the structure elucidation of unknown diterpenes. The method will also be of general use for gene function discovery, pathway reconstitution and metabolic engineering of diterpenoid biosynthesis in plants.
PMCID: PMC3878842  PMID: 24330621
Diterpene synthase; Agrobacterium; Transient protein expression; Nicotiana benthamiana

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