Salvia officinalis / Sage
Salvia miltiorrhiza / Dan Shen
Pharmacological properties of Salvia officinalis and its components
Ahmad Ghorbani et al
Salvia officinalis (Sage) is a plant in the family of Labiatae/Lamiaceae. It is native to Middle East and Mediterranean areas, but today has been naturalized throughout the world. In folk medicine, S. officinalis has been used for the treatment of different kinds of disorders including seizure, ulcers, gout, rheumatism, inflammation, dizziness, tremor, paralysis, diarrhea, and hyperglycemia. In recent years, this plant has been a subject of intensive studies to document its traditional use and to find new biological effects. These studies have revealed a wide range of pharmacological activities for S. officinalis. Present review highlights the up-to-date information on the pharmacological findings that have been frequently reported for S. officinalis. These findings include anticancer, anti-inflammatory, antinociceptive, antioxidant, antimicrobial, antimutagenic, antidementia, hypoglycemic, and hypolipidemic effects. Also, chemical constituents responsible for pharmacological effects of S. officinalis and the clinical studies on this plant are presented and discussed.
Source : Journal of Traditional and Complementary Medicine
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A network pharmacology-based study on the anti-hepatoma effect of Radix Salviae Miltiorrhizae
Yi Luo, Yu Feng, Lei Song, Gan-Qing He, Sha Li, Sha-Sha Bai, Yu-Jie Huang, Si-Ying Li, Mohammed M. Almutairi, Hong-Lian Shi, Qi Wang & Ming Hong
Radix Salviae Miltiorrhizae (RSM), a well-known traditional Chinese medicine, has been shown to inhibit tumorigenesis in various human cancers. However, the anticancer effects of RSM on human hepatocellular carcinoma (HCC) and the underlying mechanisms of action remain to be fully elucidated.
In this study, we aimed to elucidate the underlying molecular mechanisms of RSM in the treatment of HCC using a network pharmacology approach. In vivo and in vitro experiments were also performed to validate the therapeutic effects of RSM on HCC.
In total, 62 active compounds from RSM and 72 HCC-related targets were identified through network pharmacological analysis. RSM was found to play a critical role in HCC via multiple targets and pathways, especially the EGFR and PI3K/AKT signaling pathways. In addition, RSM was found to suppress HCC cell proliferation, and impair cancer cell migration and invasion in vitro. Flow cytometry analysis revealed that RSM induced cell cycle G2/M arrest and apoptosis, and western blot analysis showed that RSM up-regulated the expression of BAX and down-regulated the expression of Bcl-2 in MHCC97-H and HepG2 cells. Furthermore, RSM administration down-regulated the expression of EGFR, PI3K, and p-AKT proteins, whereas the total AKT level was not altered. Finally, the results of our in vivo experiments confirmed the therapeutic effects of RSM on HCC in nude mice.
We provide an integrative network pharmacology approach, in combination with in vitro and in vivo experiments, to illustrate the underlying therapeutic mechanisms of RSM action on HCC.
Source : Journal Chinese Medicine
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Diterpenoid Tanshinones, the extract from Danshen (Radix Salviae Miltiorrhizae) induced apoptosis in nine human cancer cell lines
ObjectiveTo identify the active anti-tumor constituents in the extract from Danshen (Radix Salviae Miltiorrhizae) and investigate the mechanisms underlying the actions.
MethodsFirst, we introduced a two-step counter-current chromatography to extract the therapeutically active diterpenoid, tanshinone from Danshen (Radix Salviae Miltiorrhizae). The cholecystokinin (CCK-8) method was used to evaluate the inhibitory effect of diterpenoid tanshinone in liver cancer QGY-7703, lung cancer PC9, lung cancer A549, gastric cancer MKN-45, gastric cancer HGC-27, colon cancer HCT116, myeloma cellU266/RPMI8226, and human breast cancer MCF-7 in vitro. Fluorescence staining was used to observe the cytotoxicity ofditerpenoid tanshinone on PC9 cells. The Western blot was used to detect apoptosis-related protein poly ADP-ribose polymerase (PARP), cysteinyl aspartate specific proteinase3/9 (caspase3/9), and cleaved-cysteinyl aspartate specific proteinase3/9 (cleaved-caspase3/9). The endoplasmic reticulum stress-related activating transcription factor 4 (ATF4), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), and phosphorylated jun amino-terminal kinase (p-JNK), and caspase-12 were also analyzed using the Western blot.
ResultsDiterpenoid tanshinone inhibited the nine human tumor cell lines, with an IC50 of 4.37–29 μg/mL, with the PC9 and MCF-7 displaying the lowest values. Fluorescence staining showed a lethal effect of diterpenoid tanshinone on PC9 cells. The Western blot showed that the expression of caspase3/9 protein and ATF-4 protein decreased gradually. However, the PARP, cleaved-caspase 3/9 and the expression of p-eIF2 α, P-JNK, and caspase-12 increased gradually, in a dose-dependent fashion.
ConclusionWe successfully introduced a two-step counter-current chromatography method to extract diterpenoid tanshinone, and demonstrated its antitumor activity. Diterpenoid tanshinone can induce apoptosis in nine human cancer cell lines.
Source : Journal of Traditional Chinese Medicine
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Salvia miltiorrhiza extract protects white matter and the hippocampus from damage induced by chronic cerebral hypoperfusion in rats
Min-Soo Kim14, Ji Hye Bang12, Jun Lee15, Hyeon Woo Kim3, Sang Hyun Sung3, Jung-Soo Han4 and Won Kyung Jeon1*
Salvia miltiorrhiza (SM), an herbal plant, is traditionally used in the treatment of cardiovascular and cerebrovascular diseases in Asian countries. SM has multiple biological effects including anti-inflammatory activity. The present study is aimed at investigating the effects of SM extract in rats with chronic cerebral hypoperfusion.
Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). The rats were divided into 3 groups: sham-control, BCCAo treated with vehicle, and BCCAo treated with SM extract. Vehicle or SM extract (200 mg/kg) were administered daily by oral gavage beginning on day 21 after BCCAo and continuing to day 42. Immunohistochemical analyses were used to measure Iba-1-positive microglia and myelin basic protein (MBP) in white matter and hippocampal tissue. In addition, the expression levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, and the toll-like receptor (TLR) pathway in the hippocampus, were analyzed by western blot.
Administration of SM extract attenuated the activation of microglial cells in the white matter and hippocampus after BCCAo. SM extract also prevented neuroinflammation after BCCAo by reducing hippocampal levels of TNF-α, IL-1β, and IL-6, and increasing the reduced levels of MBP in the white matter and hippocampus. Further, the administration of SM extract alleviated the up-regulation of hippocampal TLR4 and myeloid differentiation primary response gene 88 (MyD88) in rats with chronic BCCAo.
Our findings suggest that SM may be a promising therapeutic candidate in vascular dementia because of its protective effects against damage to the white matter and hippocampus after BCCAo.
Source : BMC Complementary and Alternative Medicine
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Hepatoprotective effect of cryptotanshinone from Salvia miltiorrhiza in D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.
Fulminant hepatic failure (FHF) is a life-threatening clinical syndrome and characterized by coagulopathy, jaundice and multisystem organ failure and a very high mortality, even though there is still no available therapy except liver transplantation limited by the chronic shortage of donor livers (Van Thiel et al. 2002).
D-Galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatitis in mice is a commonly used test model with endotoxemic shock and fulminant hepatic failure, which is similar to fulminant hepatic failure in clinic (Hishinuma et al. 1990). In the GalN/LPS model, LPS, as the bacterial cell wall component is used to initiate the inflammatory response. Because rodents are less sensitive to LPS exposure than humans, LPS is combined with the amino sugar GalN to sensitize the animals. In response to the infection in mammals LPS is detected by immune cells such as monocytes, macrophages and hepatic Kupffer cells (Liaskou et al. 2012). The combined exposure to GalN/LPS activates Kupffer cells to produce tumor necrosis factor (TNF)-[ALPHA], consequently results in hepatocyte apoptosis, in the early stages of the LPS-induced liver injury in GalN-sensitized mice (Jaeschke et al. 1998). Then in the later stages of liver injury neutrophils transmigrate and attack hepatocytes, and eventually cause massive hepatocyte necrosis and multiorgan failure (Ramaiah and Jaeschke 2007).
Mitogen-activated protein kinases (MAPKs) family including p38 kinase, c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) serve to regulate diverse cellular responses to extracellular stimuli, and modulate various cellular activities including gene expression, mitosis, differentiation and cell survival/apoptosis. With regard to the regulation of MAPKs, it is well known that nuclear factor (NF)-[kappa]B is an important transcriptional factor involved in the expression of TNF-[alpha] and interleukin (IL)-1 (Aggarwal 2004). In unstimulated cells, NF-[KAPPA]B is sequestered in an inactive form in the cytoplasm bound to inhibitory I[kappa]B protein. Stimulation leads to the rapid phosphorylation, ubiquitination, and degradation of I[KAPPA]B, which frees NF-[kappa]B to translocate to the nucleus and activate the transcription of proinflammatory genes (Karin and Ben-Neriah 2000). Therefore, an insight into the regulation of signaling pathways by MAPKs and NF-[kappa]B is indispensable for developing a treatment based on their inhibition.
Despite an increasing need for agents to protect the liver from damage, much less modern medicine is reliable regarding how to protect liver from diverse risks. Therefore, intense attention has been devoted to natural sources for the prevention and treatment of various liver diseases. Components from natural products used in folk herbs are expected to be therapeutically effective and have much lower toxicity when clinically used. Recently, we screened a numbers of natural substances, which are used traditionally for liver diseases (Lian et al. 2010b; Nan et al. 2004; Wan et al. 2010). Especially, we have reported that, in murine macrophage 264.7, cryptotanshinone (CTN) effectively inhibited LPS-triggered TLR4 signaling and NF-[kappa]B downstream pathways (Li et al. 2011). Cryptotanshinone is a major active Iipid-soluble constituent of Salvia miltiorrhiza Bunge (reputed "Danshen") (Zhong et al. 2009), which is commonly used in the Traditional Chinese Medicine system. It was reported that Salvia m. ameliorates cirrhosis and portal hypertension, and also protects against doxorubicin-induced hepatic toxicity (Wagner and Ulrich-Merzenich 2013 and references therein). Cryptotanshinone possesses anti-cancer, antiinflammatory and anti-oxidative activities (Lee et al. 2009; Li et al. 2011; Tang et al. 2011). In previous research, we also found that CTN significantly increased the survival rate against LPS challenge in GalN-sensitized mice. Additionally Park et al. (2009) have reported that cryptotanshinone-containing purified extract of Salvia m. protects hepatocytes from GalN-induced liver toxicity in vitro. Those together with previous in vitro results (Li et al. 2011) intrigued us to further investigate whether cryptotanshinone could attenuate GalN/LPS-induced fulminant liver failure in mice.
Source : International Journal of Phytotherapy and Phytopharmacology
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A Comparison of the Anti-Staphylococcus aureus Activity of Extracts from Commonly Used Medicinal Plants
Rebecca Snowden, ND,1Heather Harrington, ND,1,2Kira Morrill, ND,1LaDeana Jeane, ND,1Joan Garrity, ND,1Michael Orian, ND,1Eric Lopez, ND,1Saman Rezaie, ND,1Kelly Hassberger, ND,1Damilola Familoni, ND,1Jessica Moore, ND,1Kulveen Virdee, ND,1Leah Albornoz-Sanchez, ND,1Michael Walker, ND,1Jami Cavins, ND,1Tonyelle Russell, ND,1Emily Guse, ND,1Mary Reker, ND,1Onyria Tschudy, ND,1Jeremy Wolf, ND,1Teresa True, ND,1Oluchi Ukaegbu, ND,1Ezenwanyi Ahaghotu, ND,1Ana Jones, ND,1Sara Polanco, ND,1Yvan Rochon, PhD,1,3Robert Waters, PhD,1,2and Jeffrey Langland, PhD1,2
Background:Resurgences of Staphylococcus aureus infection continue globally, with antibiotic resistance increasing dramatically, making these infections more difficult to treat.S. aureus epidemics impose public health threats, and economic burdens on health care costs worldwide, presenting challenges modern medicine struggles to control.
Objective:In order to answer today’s call for effective treatments against S. aureus, we evaluated and compared various botanical extracts that have historically been suggested as useful for their antimicrobial properties against S. aureus.
Design:Briefly,S. aureus cultures were treated with selected botanical extracts and the minimum inhibitory concentration (MIC) determined. In addition, to obtain more quantitative measures on bacterial growth, 24-hour growth studies were done to examine the temporal activity and stability of various botanicals on bacterial replication.
Results:The antimicrobial activity observed for the botanical extracts used in this comparative evaluation of efficacy included both bacteriostatic and bacteriocidal activity against S. aureus. Highly effective botanicals including Salvia officinalis, Eucalyptus globulus,Coleus forskohlii,Coptis chinensis, Turnera diffusa, and Larrea tridentata exhibited MIC values ranging from 60 to 300lg/mL and a 106-fold reduction in bacterial replication.Arctostaphylos uva-ursi and Allium sativum were slightly less effective, exhibiting MIC values ranging from 90 to 400lg/mL and a 105-fold reduction, while Anemopsis californica gave MIC value of 360lg/mL and a 104-fold reduction in bacterial replication. Many botanicals, especially at lower doses, had an initial inhibitory effect followed by a recovery in bacterial replication. Such botanicals included E. globulus,C. chinensis,T. diffusa,A. californica, and Berberis vulgaris.
Conclusions:Our data demonstrate that S. officinalis, E. globulus, C. forskohlii, A. uva-ursi, C. chinensis,T. diffusa, A. californica, A. sativum,and L. tridentataall show promising direct antimicrobial activity against S. aureus.For many of these botanicals, strong bacteriocidal activity was observed at higher concentrations,but even at lower concentrations, bacteriostatic activity was evident. Other botanicals including B. vulgaris,Baptisia tinctoria, and Glycyrrhiza glabra showed moderate activity against S. aureus, while Schisandra chinensis, Echinacea angustifolia, and Polygonum multiflorum were shown to be ineffective
Source : Journal Alternative and Complementary Medicine
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Salvia miltiorrhiza (Danshen) injection ameliorates iron overload-induced cardiac damage in mice
.Zhang JP1, Zhang YY, Zhang Y, Gao YG, Ma JJ, Wang N, Wang JY, Xie Y, Zhang FH, Chu L.
The traditional Chinese medicinal herb Danshen (Salvia miltiorrhiza), first recorded in the "Shen Nong's Herbal Classic", has long been used to treat cardiovascular conditions, although the mechanism(s) underlying its effects remain unclear. Here, an iron dextran injection (50 mg · kg⁻¹ per day) was delivered intraperitoneally to establish a mouse model for investigating the ameliorative effects of Danshen injection (low dose at 3 g · kg⁻¹ per day or high dose at 6 g · kg⁻¹ per day) on iron overload-induced cardiac damage. The iron-chelating agent deferoxamine (100 mg · kg⁻¹ per day) was administered as a positive control. The main constituents of Danshen injection, salvianic acid A (danshensu), protocatechuic aldehyde, and salvianolic acid B, were quantified at concentrations of 2.15, 0.44, and 1.01 mg · mL⁻¹, respectively, using HPLC with UV detection. Danshen injection significantly lowered cardiac iron deposition and the concentration of the lipid oxidation product malondialdehyde, as well as improved cardiac superoxide dismutase and glutathione peroxidase levels in iron-overloaded mice. Serum levels of creatine kinase, creatine kinase isoenzyme, and lactate dehydrogenase in the iron-overloaded mice were significantly elevated (up to ~ 160 %), whereas their activities were downregulated by Danshen injection by 25 ~ 35 % at the high dose and by ~ 20 % at the low dose. Morphological changes of cardiac tissue analyzed by hematoxylin and eosin staining indicated that lesions induced by iron overload could be ameliorated by Danshen injection dose-dependently. Altogether, these results illustrated that the protective effects of Danshen injection were at least in part due to decreased iron deposition and inhibition of lipid peroxidation.
Source : Planta Medica
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Salvia miltiorrhiza Injection Ameliorates Renal Damage Induced by Lead Exposure in Mice
Lei Li,1,2 Yuanyuan Zhang,1 Juanjuan Ma,1 Weichong Dong,3 Qiongtao Song,1 Jianping Zhang,1 and Li Chu1
1Department of Pharmacology, School of Basic Medicine, Hebei Medical University, 326 Xinshi South Road, Shijiazhuang, Hebei 050091, China
2Department of Internal Medicine, Baoding First Hospital of Traditional Chinese Medicine, Yuhua Western Road, Baoding, Hebei 071000, China
3Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, Hebei 050017, China
Exposure to lead (Pb) can induce kidney injury and our recent studies have found that Salvia miltiorrhiza (SM) injection, a traditional Chinese medicine, could protect against the organ injury induced by iron overload. This study was designed to investigate the protective effects of SM injection on nephrotoxicity induced by Pb acetate in mice and to elucidate the potential mechanism(s). Healthy male mice were randomly divided into four groups: control, Pb, low-dose Salvia miltiorrhiza (L-SM), and high-dose Salvia miltiorrhiza (H-SM). SM injection dose dependently reduced the Pb accumulation in the kidney, decreased kidney coefficients, and ameliorated renal structure and function from the morphology analysis. Meanwhile, SM administration downregulated serum levels of blood urea nitrogen (BUN) and creatinine (CR), decreased malondialdehyde (MAD) content, and increased activities of super oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the kidney homogenate. Moreover, SM injection reduced the level of renal apoptosis by immunohistochemical staining analysis. Our findings implicate the therapeutic potential of SM injection for Pb-induced nephrotoxicity, which were at least partly due to the decrease of Pb accumulation, inhibition of lipid peroxidation, and suppression of renal apoptosis. These results provided preliminary experimental support for Danshen as a therapeutic drug for Pb poisoning diseases.
Source : The Scientific World Journal
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Cardiovascular Protective Effects of Adjunctive Alternative Medicine (Salvia miltiorrhiza and Pueraria lobata )in High-Risk Hypertension
K. S. Woo,1,2,3Thomas W. C. Yip,4Ping Chook,1,2S. K. Kwong,5C. C. Szeto,2June K. Y. Li,4Alex W. Y. Yu,5William K. F. Cheng,1Thomas Y. K. Chan,2K. P. Fung,1,6andP.C.Leung1
1Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong
2Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
3Room 186, Science Centre South Block, School of Life Sciences, Biochemistry Programme,The Chinese University of Hong Kong, Hong Kong
4Department of Medicine, Yan Chai Hospital, Hong Kong
5Department of Medicine, Alice Ho Miu Ling Nethersole Hopsital, Hong Kong
6School of Medical Sciences, The Chinese University of Hong Kong, Hong Kong
Introduction. Hypertension in association with diabetes (DM), renal impairment (RI), and left ventricular hypertrophy (LVH)increases the risk of future cardiovascular events. We hypothesize, traditional herbal medicines Danshen and Gegen (D&G) have beneficial effects on atherogenesis in these high-risk hypertensive subjects.
Subjects and Methods. 90 asymptomatic hypertensive subjects associated with LVH (63.3%), DM (62.2%), or RI (30%) were randomized to receive D&G herbal capsules 1gm/day,2gm/day, or identical placebo capsules in double-blind and parallel fashion for 12 months. Brachial flow-mediated dilation(endothelium-dependent dilation, FMD) and carotid intima-media thickness (IMT) were measured by ultrasound. All data were analyzed using the Statistical Package for Social Sciences in Windows 16.0.
Results.Their mean age was 55±8years, and 74.4% were male. After 12 months of adjunctive therapies and compared with baseline, there were no significant changes in blood pressure,heart rate, hematological, glucose, and creatinine profiles in both placebo and D&G groups. FMD improved significantly during D&G (𝑃=0.0001) and less so after placebo treatment (𝑃=0.001). There was a mild but significant decrease in carotid IMT after D&G (𝑃<0.001) but no significant changes after placebo. A trend of better improvement in FMD after higher versus lower D&G dosages was seen. D&G were well tolerated, with no significant adverse events or blood biochemistry changes.
Conclusion.D&G adjunctive treatment was well tolerated and significantly improved atherogenesis in high-risk hypertensive patients, with potential in primary atherosclerosis prevention
Source : Evidence Based Complementary and Alternative Medicine
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Therapeutic effects of water soluble danshen extracts on atherosclerosis.
Cho YH, Ku CR, Hong ZY, Heo JH, Kim EH, Choi DH, Kim D, Kim AJ, Lee CS, Jung M, Lee HC, Seo M, Lee EJ.
Severance Hospital Integrative Research Institute for Cerebral & Cardiovascular Diseases, Severance Hospital, Seoul 120-752, Republic of Korea.
Danshen is a traditional Chinese medicine with many beneficial effects on cardiovascular diseases. The aim of this study was to evaluate the mechanisms responsible for the antiatherogenic effect of water soluble Danshen extracts (DEs). Rat vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were treated with DE. To evaluate the effects of DE in vivo, carotid balloon injury and tail vein thrombosis were induced in Sprague-Dawley (SD) rats and iliac artery stent was induced in New Zealand white rabbits. The inhibitory action of DE on platelet aggregation was confirmed with an impedance aggregometer. DE inhibited the production of reactive oxygen species, and the migration and proliferation of platelet-derived growth factor-BB stimulated VSMCs. Furthermore, DE prevented inflammation and apoptosis in HUVECs. Both effects of DE were reconfirmed in both rat models. DE treatment attenuated platelet aggregation in both in vivo and ex vivo conditions. Pretreatment with DE prevented tail vein thrombosis, which is normally induced by κ-carrageenan injection. Lastly, DE-treated rabbits showed decreased in-stent restenosis of stented iliac arteries. These results suggest that water soluble DE modulates key atherogenic events in VSMCs, endothelial cells, and platelets in both in vitro and in vivo conditions.
Source : Evid Based Complement Alternat Med. 2013; 2013: 623639. Published online 2013 January 16. doi: 10.1155/2013/623639
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Comparative in vitro study on the anti-herpetic effect of phytochemically characterized aqueous and ethanolic extracts of Salvia officinalis grown at two different locations.
Schnitzler P, Nolkemper S, Stintzing FC, Reichling J.
Department of Virology, Hygiene Institute, University of Heidelberg, Heidelberg, Germany.
Aqueous and ethanolic extracts of Salvia officinalis (Lamiaceae) from two different locations (Garden and Swabian Mountains) were examined in vitro on RC-37 cells for their antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) using a plaque reduction assay. The 50% inhibitory concentrations ([IC.sub.50]) of the extracts for HSV plaque formation were determined in dose-response studies. All extracts tested revealed a high virucidal activity against free HSV-1 and HSV-2. The experimental data exhibited a significant higher sensitivity of HSV against the extracts derived from Garden in comparison with those from Swabian Mountains. The most active one was the Garden 20% ethanol extract with [IC.sub.50] values of 0.18 [micro]g/ml for HSV-1 and 0.04 [micro]g/ml for HSV-2. In order to identify the mode of antiviral action, the extracts were added to the host cells (RC-37) or viruses at different stages of infection. Independently of the location, both types of herpes viruses were considerably inactivated after treatment with the extracts prior to cell infection. Plaque formation was significantly reduced by >90% for HSV-1 and by >99% for HSV-2. Pretreatment of the host cells with both Garden and Swabian Mountains 20% and 40% ethanolic extracts prior to virus infection revealed a strong reduction of HSV-2 plaque formation by 94% and 70% (Garden) and 99% and 45% (Swabian Mountains), respectively. In time-activity studies with free HSV-1 over a period of 2 h, a clearly time-dependent activity was demonstrated whereby the ethanolic extracts of both locations revealed a much higher activity than the aqueous ones. The 20% ethanolic extracts of both locations are of special interest and were effective when added to host cells and free virus. A topical application with a dual mode of action would be ideal against recurrent herpes infections.
Source : Phytomedicine. 2008 Jan;15(1-2):62-70
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Metabolomic profiles of myocardial ischemia under treatment with salvianolic acid B
Yonghai Lu1,3, Yue Zheng2,4, Xinru Liu1, Xu Liang1, Saiming Ngai3, Tiejun Li2* and Weidong Zhang1*
1 Department of Medicinal Chemistry of Nature Product, School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, China
2 Department of Pharmacology, School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, China
3 School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, China
4 Institute for Drug and Instrument Control of Health Department, General Logistics Department of the Chinese People's Liberation Army, Beijing 100071, China
Background Radix Salvia miltiorrhiza (Danshen) has been used as a principal herb in treating cardiovascular diseases in Chinese medicine. Salvianolic acid B (SA-B), a water-soluble active component of Danshen, was found to have anti-myocardial ischemia (anti-MI) effect. This study aims to investigate mechanisms of SA-B on MI.
Methods Five conventional Western medicines (isosorbide dinitrate, verapamil, propranolol, captopril and trimethazine) with different mechanisms for treating cardiovascular diseases were selected as positive references to compare with SA-B in changing of the metabolomic profiles in MI rats under treatment. Potential mechanisms of SA-B were further investigated in H9C2 cell line.
Results The metabolomic profiles between SA-B- and propranolol-treated MI rats were similar, since there was a big overlap between the two groups in the PLS-DA score plot. Finally, it was demonstrated that SA-B exhibited a protective effect on MI mainly by decreasing the concentration of cyclic adenosine monophosphate (cAMP) and Ca2+ and inhibiting protein kinase A (PKA).
Conclusion SA-B and propanolol exhibited similar metabolomic profiles, indicating that the two drugs might have a similar mechanism.
Source : Chinese Medicine
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Sage, also known as common sage or garden sage, is a perennial that grows to a height of 3 feet with blue-violet blooms in summer.1,2 Salvia officinalis originated in Southeastern Europe in the area that is now known as Albania and Bosnia.3 Today, although cultivated in some European countries (e.g., Albania, Bulgaria, Croatia, Germany, Poland, Romania, Serbia and Montenegro, and Spain) and the United States, more than half of the world’s supply is still wild-collected (mainly in Albania, Bosnia and Herzegovina, Croatia, Serbia and Montenegro), with increasing amounts being wild-collected under organic certification.4-10
Sage leaves are chewed whole; dried and ground into a powder; prepared as a fluid extract, tincture, or essential oil; or pressed fresh for the juice.3 The genus Salvia is fairly large, containing hundreds of species not addressed in this profile, which are employed for a wide variety of applications in traditional medicine in the regions to which they are native.11 Aside from S. officinalis, the most notable of these are Chinese sage root (dan shen; S. miltiorrhiza) and S. divinorum leaves, the reputed hallucinogen from Mexico.11
History and Cultural Significance
The genus name Salvia derives from the Latin salvere, meaning “to save,” perhaps referring the healing properties of plants in this genus.3,12 Salvia officinalis was used medicinally by ancient societies in Greece, Egypt, and Rome.3 Traditionally, it was employed to increase fertility, stop bleeding, heal minor skin wounds, treat hoarseness or cough, and improve memory function.3 The English herbalist John Gerard (1545-1607) claimed that sage (usually a tea made from the leaves) was good for the head, brain, and memory,13 and the physician/herbalist Nicholas Culpeper (1616-1654) also thought that it improved memory.14
In India, sage leaves were also used to treat intestinal gas, upset stomach, and infections of the mouth, nose, and throat.3 Historically, sage has been used to promote regularity in a woman’s menstrual cycle and to decrease breast milk production to facilitate weaning.1,2 Since ancient times in most Mediterranean countries, sage has been popular as a culinary herb for its powerful and intense flavor, especially in meat and poultry dishes.12
Current uses of sage include the following: indigestion, treatment of inflammation of the mouth and throat, and excessive sweating, including that associated with peri-menopause; relief of pressure spots that result from the use of a prosthesis; and as a flavoring for food.1-3,11-12,15 Sage oil has also been employed as a fragrance in soaps and perfumes.1,3
In 1985, the German Commission E approved the use of sage internally for dyspepsia (upset stomach or indigestion) and excessive perspiration, and externally for inflammation of the nose and throat.3 One of the constituents of sage, salvin (a phenolic acid), has antimicrobial effects against Staphylococcus aureus,1 a common bacteria responsible for skin and upper-respiratory tract infections. Sage has also shown strong antioxidant properties.1,2 The German Standard License for sage leaf infusion indicates its use for inflammation of the gums and the mucous membranes of the mouth and throat, for pressure spots caused by prostheses, and in supportive treatment of gastrointestinal catarrh (inflammation of the mucous membranes).2
In 2009, the European Medicines Agency (EMA) published a final monograph which supersedes monographs of EU national authorities (including the German monographs) for the registration of traditional herbal medicinal products in the European Community that contain sage as an active ingredient.16 Traditional uses approved for sage leaf (dry extract, herbal tea, liquid extract and tincture) are (a) for symptomatic treatment of mild dyspeptic complaints such as heartburn and bloating; (b) for relief of excessive sweating; (c) for the symptomatic treatment of inflammations in the mouth and throat; and (d) for relief of minor skin inflammations.10 A prerequisite of registration is that the quality complies with the corresponding quality standards monographs of the European Pharmacopoeia (e.g., Sage Leaf PhEur or Sage Tincture PhEur). Concerning sage essential oil, the EMA has concluded that the risks do not outweigh the benefits; thus, a European Community herbal monograph will not be developed until new evidence of clinical safety and efficacy become available.17
In the United States, sage leaf is regulated as a food ingredient and as a dietary supplement component. Sage leaf is listed as GRAS (Generally Recognized as Safe) for use as a spice, seasoning, or natural flavor,18 while sage essential oil is a GRAS flavoring agent.19 For use of the essential oil as a flavoring, a quality standards monograph for “Dalmatian Type Sage Oil” is published by the United States Pharmacopeia Convention in the Food Chemicals Codex.20 For therapeutic use, as part of the US Food and Drug Administration's (FDA) ongoing review of over-thecounter (OTC) drug products, the Dental Plaque Subcommittee of the Nonprescription Drugs Advisory Committee recently evaluated the safety and efficacy of sage oil combined with peppermint oil (Mentha x piperita, Lamiaceae). While the Subcommittee concluded that sage oil is safe for the intended use, they also concluded that there are insufficient data from controlled studies to permit final classification of the effectiveness of combined peppermint and sage oils as OTC active ingredients for the reduction of plaque and gingivitis.21
Note: Some of the studies mentioned below address S. lavandulifolia (lavandulaefolia), which is now recognized as a subspecies of S. officinalis, e.g., Salvia officinalis subsp. lavandulifolia (Vahl) Gams.22 (Unless specified otherwise, the species studied was S. officinalis.)
Based on sage’s traditional use as an aid to memory, preliminary pharmacological investigations were conducted into its bioactivity (S. officinalis and S. lavandulifolia) that led to more detailed in vitro studies which investigated the chemical constituents that might be responsible for aiding failing memory.11 Results suggested that cyclic monoterpenes 1,8-cineole and alpha-pinene, as well as camphor, were responsible for the cholinesterase inhibition witnessed. Additionally, 1,8-cineole, alpha- and beta-pinene appeared partially responsible for the antioxidant effect of sage. Because Alzheimer’s Disease (AD) is thought to be due, in part, to inflammation and damage caused by pro-oxidant compounds that act on the brain cells, and since cholinesterase inhibitors are a standard treatment for AD patients, clinical studies on sage were needed to determine if it might be an appropriate treatment for AD patients.
A 2010 clinical study investigated the effect of the essential oils of S. officinalis and other species on cognition and mood in 135 healthy adults (45 in each group of S. officinalis, S. lavandulifolia, [5 drops of each essential oil in 5 ml water, NHR Organic Essential Oils, Brighton, UK] and no aroma). 23 The S. officinalis group performed significantly better than the S. lavandulifolia and control groups on the quality of memory, specifically long-term or secondary memory with no impact on working memory performance. The authors state that they would not have predicted the non-significant difference between the S. lavandulifolia and no aroma based on previous research, but that one possible explanation could be the lack of standardization of the sage preparations. The S. officinalis findings compared favorably with those reported earlier following oral administration of sage in healthy young participants.
A randomized, placebo-controlled, double-blind, balanced, 5-period crossover study in 2008 investigated the acute effects on cognitive performance of a standardized extract of sage (either 167 or 333 mg of a 70% dried ethanolic extract, Essential Nutrition, Brough, East Yorkshire, UK) in healthy adults (n=20) between 65-90 years of age.24 The study found that administration of a standardized sage extract can improve cognitive function in healthy older people. Specifically, the authors saw dose-specific improvement in secondary memory performance for the 333 mg dose. Results corresponded to those found in earlier studies on younger populations and suggested that further investigations were warranted in larger numbers, other populations, and with different dosing regimens.
In a 2006, a double-blind, placebo-controlled, crossover study, 30 healthy participants received—on 3 separate days, 7 days apart—either 600 mg or 300 mg dried sage leaf or placebo.25 Mood was assessed predose and at 1 and 4 hours post-dose, with each mood assessment being done before and after 20 minute performance of the Defined Intensity Stress Simulator (DISS) computerized multitasking battery. Improved ratings of mood in the absence of the stressor (pre-DISS) occurred with both doses, with the 300 mg dose reducing anxiety and the 600 mg dose leading to alertness, calmness, and contentedness. Reduced anxiety disappeared upon performance of the DISS. Results corresponded to those in other dose-dependent studies, and the authors suggested that further research was warranted into the potential use of sage in treating AD and natural aging, and the mechanisms responsible for the beneficial effects.
A 2005 placebo-controlled, double-blind, balanced, crossover study investigated the effect of S. lavandulifolia on mood and cognition in healthy young volunteers (n=24, 16 female, 8 male, 18-37 years old).26 Single doses of placebo, 25 ml, and 50 ml of a standardized essential oil (Baldwins, London, UK) were given 4 times, 7 days apart. Participants were tested pre-dose and at 1, 2.5, 4, and 6 hours after dosing. Results showed consistent improvement for both doses on speed of memory, alertness, calmness, and contentedness.
In a 4-month, parallel group, placebo-controlled clinical trial in 2003 where 42 patients with mild to moderate AD were randomized to placebo or fixed dose of S. officinalis extract (1:1 in 45% alcohol, Institute of Medicinal Plants, Halejerd, Iran), the patients taking the sage extract showed a significantly better outcome on cognitive functions than placebo.27 Additionally, agitation appeared to remain more frequent in the placebo group.
Human clinical studies on other aspects of sage have also been conducted. In 2009, a trial assessed the relative efficacy of a sage/ echinacea (SE) spray and a chlorhexidine/lidocaine (CL) spray in the treatment of acute sore throat.28 The SE treatment was a little better at reducing sore throat symptoms than the CL treatment during the first 3 days (63.8% vs. 57.8% at 3 days). No differences were noticed in secondary parameters and both were well-tolerated.
A 2007 prospective, randomized, double-blind, placebo-controlled study investigated the anti-inflammatory effects of a sage extract using the ultraviolet erythema test.29 Test areas on the backs of 40 healthy volunteers were irradiated with the minimal erythema dose, then treated with 2% w/w of a commercially available sage extract (Flavex GmbH; Rehlingen, Germany), a 1% hydrocortisone control, 0.1% betamethasone control, placebo ointment, or no treatment. The sage extract significantly reduced the UV-induced erythema compared to placebo, and to a similar extent as the hydrocortisone.
A clinical study from 2001 has documented the benefits of a sage-rhubarb cream to decrease the duration of external lip eruptions caused by Herpes simplex (H. labialis).30 The same study showed that the sage-rhubarb cream was also effective at relieving the pain and swelling that patients experience with herpetic flares.
There is little specific information concerning the current market statistics for sustainable harvesting of sage. There are certified operators marketing organic wild-collected sage from European countries which requires implementation and inspection of sustainable wild-resource management plans. The European Herb Growers Association (EUROPAM) 2010 update on production of medicinal and aromatic plants (MAPs) in Europe, although not specific, indicates that commercial cultivation increased in Bulgaria while wild collection decreased; that sage remains one of the main medicinal herbs produced in Germany; and that it is still cultivated in Romania and in Greece in cooperatives.31
According to one source, Albania has traditionally been one of the world’s leading sage producers.32 It is one of Albania’s most important MAPS exports and, in 2001, 1500 tons were exported with a market value of about $2.5 million (USD).
The US imports sage leaf tracked under the 10-digit Harmonized System Tariff Code (HS Code: 1211.9091.50). In 2009, the US imported 2,294.5 metric tons (MT), down 21% from 2008 imports of 2,909.1 MT, over 55% of which is exported by Albania.33 After Albania, the second-largest supplier of sage leaf to the US is Germany. Although Germany is a producer of sage leaf, much of the German exports are likely re-exports of sage leaf originally from southeastern European countries (J. Brinckmann, e-mail, January 17, 2011).
Previous records indicate that worldwide production equaled 35 tons of sage essential oil in 1993, which was valued at $1,800,000.00.34 Morocco produced 124.5 tons of dried leaves for export in 1993, but only 81.4 tons in 1996.35
Turkey is one of the most important sage-producing countries of the world. Due to overcollection of the herb in the wild that was posing a risk to native populations, a 2-year field study was undertaken to determine which of a number of methods would produce the best seedling quality for commercial cultivation of the plant.36 The greenhouse seedbed method proved best because it resulted in the most vigorous seedling development and highest total fresh- and dry-weight herb production. A modified float system produced superior root development and less lateral root damage during transplantation. The authors stated that this was only preliminary data and that further studies were required to elucidate cultural requirements of S. officinalis.
- DerMarderosian A, Beutler JA, eds. The Review of Natural Products: The Most Complete Source of Natural Product Information. 3rd ed. St. Louis, MO: Facts and Comparisons; 2002.
- Wichtl M, ed. Brinckmann JA, Lindenmaier MP, trans. Herbal Drugs and Phytopharmaceuticals. 3rd ed. Stuttgart: Medpharm GmbH Scientific Publishers; 2004.
- Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded Commission E Monographs. Austin, TX: American Botanical Council; Newton, MA: Integrative Medicine Communications; 2000.
- Foster S. Medicinal plants of Montenegro. HerbalGram. 2006;72:48-54.
- European Herb Growers Association. Production of medicinal and aromatic plants in Europe. Status 2010. Available at: www.europam.net/ index.php?option=com_content&view=article&id=6:inventory-production-of-mapsq&catid=8:inventory-production-of-mapsq&Itemid=11. Accessed January 17. 2011.
- Kathe W, Honnef S, Heym A. Medicinal and Aromatic Plants in Albania, Bosnia-Herzegovina, Bulgaria, Croatia and Romania: A study of the collection of and trade in medicinal and aromatic plants (MAPs), relevant legislation and the potential of MAP use for financing nature conservation and protected areas. Bonn, Germany: German Federal Agency for Nature Conservation. 2003. Available at: www.bfn.de/fileadmin/MDB/documents/skript91.pdf. Accessed January 17, 2011.
- Redzic S. Wild medicinal plants and their usage in traditional human therapy (Southern Bosnia and Herzegovina, W. Balkan). Journal of Medicinal Plants Research. 2010;4(11):1003-1027. Available at: www. academicjournals.org/jmpr/PDF/pdf2010/4June/Sulejman.pdf. Accessed January 17, 2011.
- Baricevic D, Bernáth J, Maggioni L, Lipman E, compilers. ECPGR Report of a working group on medicinal and aromatic plants: First Meeting, 12-14 September 2002, Gozd Martuljek, Slovenia. 2004. Available at: www.bioversityinternational.org/fileadmin/bioversity/publications/ pdfs/984.pdf?cache=1295290021. Accessed January 17, 2001.
- Censkowsky U, Helberg U, Nowack A, Steidle M. Overview of Word Production and Marketing of Organic Wild Collected Products. Geneva, Switzerland: International Trade Centre UNCTAD / WTO. 2007. Available at: www.intracen.org/organics/documents/Overview_World_ Production_Marketing_Organic_Wild_Collected_Products.pdf. Accessed January 17, 2011.
- Donnelly R, Helberg U, in cooperation with Flora and Fauna International, UK, and Pecanac D. Balkans Herbal Development Initiative — Phase 1. Final Summary Report — Bosnia and Herzegovina. Environmental and Social Assessment, Economic & Activity Mapping, Export potential of Balkan Herbs to the European Union. Prepared for Southeast Europe Enterprise Development (SEED) and The Corporate Citizenship Facility (CCF). 2003. Available at: www.ifc.org/ifcext/enviro.nsf/AttachmentsByTitle/art_CCF-HDISerbMont/$FILE/HDI+Report+Serbia+and+Mo ntenegro.pdf. Accessed January 17, 2011.
- Houghton PJ. Activity and constituents of sage relevant to the potential treatment of symptoms of Alzheimer’s disease. HerbalGram. 2004;61:38
- Katzer G. Sage Gernot Katzer’s Spice Pages.1999. Available at: www.unigraz.at/~katzer/engl/Salv_off.html. Accessed April 4, 2005.
- Woodward M, ed. Gerard’s Herbal: The History of Plants. London: Senate; 1994.
- Culpeper N. Culpeper’s Complete Herbal. London; Bloomsbury Books; 1992.
- Barnes J, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health Professionals. 3rd ed. London: Pharmaceutical Press; 2007:512-514.
- European Pharmacopoeia Commission. Sage Leaf; Sage Tincture. In: European Pharmacopoeia, Seventh Edition (PhEur 7.0). Strasbourg, France: European Directorate for the Quality of Medicines. 2010; 12301232.
- European Medicines Agency (EMEA). Public statement on Salvia officinalis L., aetheroleum. London, UK: European Medicines Agency. July 15, 2010. Available at: www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2010/10/WC500098002.pdf. Accessed January 17, 2011.
- United States Food and Drug Administration (FDA). 21 CFR Part 582.10. Substances Generally Recognized as Safe. Washington, DC: National Archives and Records Administration; 2010. Available at: www. gpo.gov/fdsys/pkg/CFR-2010-title21-vol6/pdf/CFR-2010-title21-vol6sec582-10.pdf. Accessed January 18, 2010.
- United States Food and Drug Administration (FDA). 21 CFR Part 582.20. Substances Generally Recognized as Safe. Washington, DC: National Archives and Records Administration; 2010. Available at: www. gpo.gov/fdsys/pkg/CFR-2010-title21-vol6/pdf/CFR-2010-title21-vol6sec582-20.pdf. Accessed January 18, 2011.
- United States Pharmacopeial Convention. Dalmatian Type Sage Oil. In: Food Chemicals Codex 7th Edition. Rockville, MD: United States Pharmacopeial Convention. 2011;900-901.
- United States Food and Drug Administration (FDA). 21 CFR Part 356. Oral Health Care Drug Products for Over-the-Counter Human Use; Antigingivitis/Antiplaque Drug Products; Establishment of a Monograph. Federal Register. May 29, 2003;68(103);32232-32287. Available at: www.gpo.gov/fdsys/pkg/FR-2003-05-29/pdf/03-12783.pdf. Accessed January 17, 2011.
- Salvia officinalis subsp. lavandulifolia (Vahl) Gams. The Plant List. Available at: http://www.theplantlist.org/tpl/record/kew-376277. Accessed January 6, 2011.
- Moss L, Rouse M, Wesnes KA, Moss M. Differential effects of the aromas of Salvia species on memory and mood. Hum Psychopharmacol. July 2010;25(5):388-396.
- Scholey AB, Tildesley NTJ, Ballard CG, et al. An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers. Psychopharmacology. 2008;198:127-139.
- Kennedy DO, Pace S, Haskell C, Okello EJ, Milne A, Scholey AB. Effects of cholinesterase inhibiting sage (Salvia officinalis) on mood, anxiety and performance on a psychological stressor battery. Neuropsychopharmacology. 2006;31:845-852.
- Tildesley NTJ, Kennedy DO, Perry EK, Ballard CG, Wesnes, KA, Scholey AB. Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers. Physiol Behav. 2005;83:699-709.
- Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, and Khani M. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind randomized placebo-controlled trial. J Clin Pharm Ther. 2003;28:53-59.
- Schapowal A, Berger D, Klein P, Suter A. Echinacea/sage or chlorhexidine/lidocaine for treating acute sore throats: a randomized double-blind trial. Eur J Med Res. September 1, 2009;14(9):406-412.
- Reuter J, Jocher A, Hornstein S, Mönting JS, Schempp CM. Sage extract rich in phenolic diterpenes inhibits ultraviolet-induced erythema in vivo. Planta Med. September 2007;73(11):1190-1191.
- Saller R, Buechi S, Meyrat R, Schmidhauser C. Combined herbal preparation for topical treatment of Herpes labialis. Forschende Komplementarmedizin und Klassische Naturheilkunde. 2001;8:373-382.
- European Herb Growers Association (EUROPAM)> Production of Medicinal and Aromatic Plants in Europe. EUROPAM. European Herb Growers Association. Available at: www.europam.net/index.php?option=com_content&view=article&id=6&Itemid=11. Accessed January 7, 2011.
- Search for the Origin of Medicinal and Useful Plants in Albania: a scientific expedition on Phytotherapy. Primrose Laboratories website. Available at: www.tangatanga.com/somupa/profile/. Accessed January 7, 2011.
- 2009 Sage Import Statistics. United States Department of Commerce. United States Census Bureau. Foreign Trade Statistics.
- U.S. Imports of Sage Leaf (HS 1211.9091.50). In: Global Agricultural Trade Systems (GATS) database. United States Department of Agriculture (USDA) Foreign Agricultural Service (FAS). Available at: http://www.fas.usda.gov/gats. Accessed January 17, 2011
- Kintzios SE, ed. Sage: The Genus Salvia. Amsterdam; Harwood Academic Publishers: 2000.
- Çalişkan Ö, Ayan AK, Çirak C. Seedling quality of common sage (Salvia officinalis L.) as affected by seedling production methods. Communications in Biometry and Crop Science. 2006;1(2):106-110. Available at: http://agrobiol.sggw.waw.pl/~cbcs/articles/CBCS_1_2_6.pdf. Accessed January 7, 2011.
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