What is danshen?Inhibition of mast cell degranulation by tans...

What is danshen?Inhibition of mast cell degranulation by tanshinones from the roo

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What is danshen?Inhibition of mast cell degranulation by tanshinones from the roo ts of Salvia miltiorrhiza?

[Key words:danshen，Inhibition of mast cell degranulation，tanshinones from the roots of Salvia miltiorrhiza，tanshinones,Tanshinone IIA，Przewalsk Sage Root，R adix Salviae Przewalskii,Salvia Przewalskii Maxim.，Salvia miltiorrhiza，Salvia, danshen，Mast cell degranulation Inhibitor,Dan-shen P.E. Tanshinones10%UV,Dan-she n P.E.Tanshinones20%UV,Tanshinone IIA 10%HPLC,Radix Salviae Miltiorrhizae P.E.,Ta nshinone IIA,Radix Salviae Miltiorrhizae P.E.,water soluble Dan-Shen P.E.Tanshino ne IIA,Salvia miltiorrhiza B,Labiatae,Salvia miltiorrhiza,Salvia powder extracts, Salvia officinalis,Salvia plebia,lichicao,Salvia chinensis,shijianchuan,Salvia ro ot p.e.,Salvia root Extracts,zidanshen,anti-tumour effect of tanshinones.]

standard powder exracts available as following:

Dan-shen P.E. Tanshinones10% UV(Radix Salviae Miltiorrhizae P.E.) Dan-shen P.E. Tanshinones20% UV(Radix Salviae Miltiorrhizae P.E.) Dan-shen P.E. Tanshinones98% UV(Radix Salviae Miltiorrhizae P.E.) Tanshinone IIA 10% HPLC(Radix Salviae Miltiorrhizae P.E.) Tanshinone IIA 20% HPLC(Radix Salviae Miltiorrhizae P.E.) Tanshinone IIA 95% HPLC(Radix Salviae Miltiorrhizae P.E.) Dan-Shen P.E.Tanshinone IIA 1.5% HPLC(Water Soluble) Dan-Shen P.E.Tanshinone IIA 2.0% HPLC(Water Soluble)

◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇◇ [Chemical Name]: Tanshinones,Tanshinone IIA [Botanical Source]:Przewalsk Sage Root; [Botanical Synoms]:Radix Salviae Przewalskii,Salvia Przewalskii Maxim.;Salvia miltiorrhiza;Salvia, danshen [Plant Part Used]: Root. [Mechanism of Action Category]: Mast cell degranulation Inhibitor.

Inhibition of mast cell degranulation by tanshinones from the roots of Salvia miltiorrhiza: Abstract:The activity-guided fractionation of the extract of the root of Salv ia miltiorrhiza B. (Labiatae, Tanshen), led to the isolation of four active comp o nents responsible for the anti-allergic activity in vitro. Among them, 15,16-dih y drotanshinone-1 and cryptotanshinone demonstrated significant inhibition of the r elease of beta-hexosaminidase from cultured RBL-2H3 cells in a dose-dependent ma n ner; the ICS, values were calculated as 16 and 36 mu M, respectively

SALVIA and the History of Microcirculation Research in China Salvia refers to the root of Salvia miltiorrhiza (see Figure 1), sometimes de scribed as Chinese sage or red sage root. Any herb of the Salvia genus may be ca l led sage, but most people are familiar with the common garden plant-and the comm o n Western kitchen herb-obtained from Salvia officinalis. There are significant d i fferences in medicinal components of the tops and roots of the Salvia plants tha t influence their uses. The Western sage leaves are used medicinally to treat dys p epsia and excessive perspiration (1). The tops of Salvia plebia (lichicao) and t h e whole plant of Salvia chinensis (shijianchuan) are used medicinally by the Chi n ese, but infrequently; the former is said to treat bleeding and turbid urine, th e latter treats swellings and infections (2). Salvia root (danshen), as employed i n Chinese medicine and the subject of the rest of this article, is different in n ature from the other sage herbs, despite the botanical relationship. Danshen was used infrequently in ancient Chinese medicine, yet it has become an important herb in modern Chinese clinical practice. The transformation of sal v ia from a rarely used and minor component of formulas to a key herb is a story t h at sheds light on the evolution of the Chinese medical tradition. A review of herb formula guides shows that salvia appears in very few traditi onal formulas that are studied by modern practitioners. The only frequently ment i oned traditional formula that includes this herb is Tianwang Buxin Dan (the Heav e nly Emperor's Heart Nourishing Pill; Ginseng and Zizyphus Formula). The prescrip t ion has been made into a popular patent remedy, mainly used for insomnia, poor m e mory, and mental agitation (see: Tianwang Buxin Dan). The formula has 16 ingredi e nts, with only a small amount of salvia, which has been included for its heart n o urishing and spirit pacifying actions. In modern Chinese clinical practice, salvia is one of the most commonly used Chinese herbs: it appears in numerous formulations, sometimes as the key ingredi e nt. In addition, salvia is sometimes given as a single herb remedy, and is even p repared in injection form for IV administration. The elevation of salvia to a ke y herb took place in two steps: recognition of salvia as a valuable blood-vitaliz i ng agent leading to incorporation of the herb in modern formulas for angina pect o ris; and then, investigations of its effectiveness in treating microcirculation d isorders, leading to its use in treating liver fibrosis and cirrhosis.

Status of Salvia In Ancient Chinese Medicine: The Chinese name for salvia, danshen, carries much meaning. Here, dan is the term used to describe cinnabar (dansha; sha = sand, depicting the small crystals

of the mineral); in this context dan refers, in part, to the deep red color of s a lvia roots, which are likened to the color of cinnabar. Beyond the color, howeve r , using this name for salvia may have been intended to convey the high value of t he herb, since cinnabar has long been regarded as the premier substance of Chine s e medicine. Red colors in Chinese herbs are usually described by the term hong ( a s in honghua: carthamus), or by chi (as in chishao: red peony); purple might als o apply (zi; salvia is sometimes called zidanshen); so using dan is a rather uniq u e designation. Shen refers to ginseng (renshen; ren = man, alluding to the man-s h aped roots), long regarded as the most highly respected herb in China (see: The m eaning of shen in renshen). Only about a dozen herbs, most of them deemed suitab l e as substitutes for ginseng, have been given the name hen. Salvia first appeared in the Shennong Bencao Jing (ca. 100 A.D.); in that tex t, the highest position for all medicinal materials was held by cinnabar and the

highest position for all herbs was ginseng (and the mushroom ganoderma). Here ar e the descriptions of properties of cinnabar, ginseng, and salvia (3): Cinnabar is sweet and slightly cold. It treats hundreds of diseases of the fi ve viscera and the body. It nurtures the essence spirit, quiets the ethereal and

corporeal souls, boosts the qi, brightens the eyes, and kills spirit demons and e vil ghosts. Protracted taking may enable one to communicate with the spirit ligh t and prevent senility. Ginseng is sweet and a little cold. It mainly supplements the five viscera. I t quiets the essence spirit, settles the ethereal and corporeal souls, checks fr i ght palpitations, eliminates evil qi, brightens the eyes, opens the heart, and s h arpens the wits. Protracted taking may make the body light and prolong life Salvia is bitter and slightly cold. It is nontoxic, treating mainly evil qi i n the heart and abdomen, continual gurgling of the intestines like water running , cold and heat, and gatherings and accumulations. It breaks concretions and elim i nates conglomerations, relieves vexatious fullness, and boosts the qi. It is evident that salvia does not have the same level of desirable propertie s nor broad uses as do cinnabar and ginseng. Like ginseng, it is said to treat e v il qi, and like cinnabar, it boosts the normal qi (an effect noted for ginseng i n all later texts). The original Tianwang Buxin Dan formulation includes all thre e : ginseng, cinnabar, and salvia; the "dan" in the formula name refers to pills c o ntaining cinnabar (modern versions of the formula often delete cinnabar because o f concerns about mercury, its main active component). Each of these three herbs w ere traditionally considered important for treating disorders of the heart, as a p plies to mental functions, and for treating hot swellings (all have a slightly c o ld nature). Thus, salvia was described in the Rihuazi Bencao (713 A.D.) this way : "Salvia nourishes the heart (mind), reinforces the will power, unblocks the gua n pulse, and cures goiter and pyrogenic infections [fire toxins]."

Modern Developments Prior To Microcirculation Theory: It was only during the 20th Century that salvia became known for its blood-vi talizing properties; until then, salvia was more commonly reputed to treat bleed i ng disorders (e.g., menstrual bleeding) than blood stasis (4). Wang Qingren (176 3 -1831), who turned attention of the Chinese medical community to the importance o f blood-vitalizing therapies, did not rely on this herb. His famous formulas, su c h as Xuefu Zhuyu Tang (Decoction for Removing Blood Stasis from the Chest; Persi c a and Achyranthes Combination), depended on other herbs to treat blood stasis, a s did most herb formulas of that time. The herbs used then, and still relied on t o day by many physicians, were the combination of persica and carthamus with the i n gredients of Si Wu Tang (Tang-kuei Four Combination: tang-kuei, peony, cnidium, a nd rehmannia; sometimes one or two of these ingredients would be deleted); the g r oup of six herbs used alone is known as Tao Hong Siwu Tang. Thus, in the book He a rt Transmission of Medicineby Liu Yiren (who lived in the 19th Century just afte r Wang Qingren), the author suggested these same ingredients for treating blood s t asis, but he makes no reference to salvia. Formal acknowledgement of the value of salvia for vitalizing blood circulatio n finally appeared in the 1930s. For example, in the book published around 1935,

Yixue Zhongzhong Canxi Lu by Zhang Xichu, there was one formula with salvia: Huo l uo Xiaoling Dan (Open the Luo Vessels and Reduce Inflammation Pills), comprised o f tang-kuei, salvia, myrrh, and frankincense (to be coated in cinnabar). This pr e scription was indicated for blood stasis with pain due to trauma, inflammatory d i sorders, and abscesses. In subsequent decades, salvia became a common ingredient

in formulas for blood stasis syndromes, particularly for the cardiac disorders t h at were increasingly affecting the elderly, marked by angina pectoris as the mai n symptom. Still, the herb was not singled out as being particularly important or

has having unique properties in relation to other herbs for blood stasis, pain, o r abscesses. Qin Bowei, a famous physician born at the turn of the 20th Century who was in strumental in the spread of TCM in modern China (after the revolution in 1949), i ncluded salvia in some of the formulas he used. He described the herb this way ( 5 ): Salvia is bitter and slightly cold and enters the channels of the heart and l iver. It quickens the blood, moves the blood, and regulates transportation of bl o od fluid. The Da Ming[Mingyi Bielu ca. 500 A.D.] and Ri Hua[Rihuazi Bencao, 713 A .D., mentioned above] refer to this as "eliminating stasis and engendering the n e w," with the implication of freeing and supplementing. Salvia is most often used

in the treatment of longstanding costal pain and hard obstruction in the early s t age. Formulas mentioned by Qin Bowei that include salvia were recommended for hear t pain in a series of case reports from his practice (5). The syndromes describe d for these patients correspond closely to angina pectoris. Research into the car d iovascular effects of salvia were initiated, and resulted in confirmation that t h e herb was suitable for treating such disorders, including stroke (6, 7, 8). Sim i lar research efforts were undertaken with crataegus (shanzha), pueraria (gegen),

ginseng, and notoginseng (sanqi), which also provided positive results. A patent

remedy with salvia as the main ingredient was developed and is still widely used

in China for treating angina: Fufang Danshen Pian, mainly comprised of salvia ex t ract, notoginseng, and borneol (a heart stimulant, classified in the traditional

herb system as a substance that eliminates phlegm obstructing the orifices of th e heart). The concept of eliminating stasis to generate new blood, as mentioned by Qin Bowei, has been described frequently in modern Chinese literature. In order for n ew blood to be generated, as this theory goes, old blood that is not vital must b e removed. Therefore, when examining cases of blood deficiency, one must determi n e if blood stasis is a root problem; if it is, then there will be little effect f rom merely providing blood nourishing herbs, but a substantial effect obtained f r om using herbs that treat blood stasis. In this sense, salvia is often compared t o Tang-kuei Four Combination (Si Wu Tang), because salvia has the effect (in the s e blood stasis cases) of both vitalizing blood and nourishing blood, just like t h e four ingredient formula (the only significant difference is that salvia has a c old nature, while Si Wu Tang is warming). The theory of vitalizing blood to gene r ate new blood has been applied to the treatment of bone marrow deficiencies, whe r e millettia (jixueteng) has been a prominent ingredient in the formulas, sometim e s combined with salvia. A relatively new area of concern for blood stasis is in relation to aging. In the theoretical framework of ancient Chinese medicine, aging was understood to b e related to a degradation of the essence (jing) that is stored in the kidney an d which helps nourish the liver yin and blood and also helps stimulate the nutrit i ve functions associated with the spleen. Decline in essence results in drying of

the blood, contraction of the ligaments, withering of the flesh, and overall red u ction in vitality, mental function, and health. During the 20th Century, possibl y due to changes in the environment, diet, and lifestyle (as well as progress in m edical research into aging), it was generally agreed that disorders associated w i th aging additionally involve blood stasis This was an idea that was first prese n ted by Xu Lingtai, a famous physician of the Qing Dynasty who wrote during the m i d-18th Century. He argued that: "Since the qi and blood of the elderly do not fl o w very well, how can they bear supplementation which keeps the evils, thus makin g difficulties with the qi and blood?" This follows the theory, developed strongl y during the Qing Dynasty period, that administering formulas comprised only of t o nics retains pathological influences (evils) within the body, rather than helpin g them to leave the body. One must rectify all imbalances in order to assure depa r ture of the adverse influences, in this case improving the circulation of qi and

blood. However, Xu's concept did not get much attention for another 200 years. Yan Dexin, a physician who learned traditional style medicine prior to the Ch inese revolution and incorporated some of the new concepts developed through mod e rn research, published works on the subject of gerontology that have been transl a ted to English under the title: Aging and Blood Stasis(23). He mainly refers to t raditional formulas from earlier centuries, modified slightly, and only occasion a lly refers to the newer uses of salvia. For example, the first modified formula m entioned in his book is Wang Qingren's Xuefu Zhuyu Tang to which salvia (15 gram s /day in decoction) has been added. This formula is used for the general purpose o f treating poor circulation of qi and blood in the elderly. Applying the theory o f Xu Lingtai, in treating acute ailments such as common cold, he recommends addi n g salvia (9 grams/day in decoction) to the standard formulas that dispel wind-co l d or wind-heat. Even so, like most doctors trained prior to the introduction of m icrocirculation research, he mainly relies on blood vitalizing herbs other than s alvia.

Microcirculation Research

One of the important steps leading to more widespread use of salvia was the d evelopment of a concept new to the Chinese system: microcirculation. Since ancie n t times, Chinese doctors have known the importance of blood circulation. Indeed,

the whole system of meridians (jingluo; major and branch vessels) was based on a n attempt to map the blood vessels (see: Drawing a concept: jing), and to influen c e the circulation within them by using acupuncture, moxibustion, and herb therap i es. A well-known saying regarding the circulation is: "The qi moves the blood; t h e blood carries the qi." Put another way, the qi and blood flow together through

the vessels, including the major vessels (jing, mainly arteries) and the minor v e ssels (luo, mainly veins). Within this flow of qi and blood, one can distinguish

two types of qi: the nutritive qi (yingqi) and the defensive qi (weiqi). The nut r itive qi is said to flow within the vessels intermingled with the blood, while t h e defensive qi is said to flow at the surface of the vessels. The concept of mic r ocirculation merely adds yet another dimension to the description, and refers pr i marily to the flow of blood through tiny vessels invisible to the naked eye, suc h as the capillaries. Since these tiny vessels could not be visualized by examine r s in the past, they were only described as part of modern scientific investigati o ns into human physiology. Western research into the dynamics of capillary bed fl o w was undertaken during the 1960s; Chinese investigations began about a decade l a ter. Capillaries are the part of the vascular system that distributes blood carrie d within the large vessels (arteries) to the tissues of the body. The capillarie s are so fine that they generally permit no more than one blood cell through at a

time, and are linked to the large vessels through intermediaries, called arterio l es. The capillary walls, unlike those of arteries and veins, are permeable: nutr i ents, oxygen, and other blood constituents are able to leave the capillaries and

enter the surrounding cells, while waste materials (including carbon dioxide) ar e able to enter the capillaries and be flushed away from the surrounding cells. A

capillary can only provide these services to a depth of a few cells, so the body

is completely enmeshed in a system of capillaries. The characteristics of fluid f low through these capillaries are different than through the major vessels due t o their small size and their permeability. At a Chinese herb conference held in Hong Kong in 1984, there was a special s ession devoted to microcirculation, following up on the new research on the subj e ct in China. A collaborating team of Dr. R.J. Xiu of the Research Center for Mic r ocirculation (Chinese Academy of Medical Science, Beijing) and M. Intaglietta, o f the Department of Applied Mechanics, Engineering Sciences, and Bioengineering ( U niversity of California, San Diego), provided an overview (9). They introduced t h e subject by describing the capillary bed system and arterioles without mentioni n g them by name: The microcirculation is the principal avenue for the delivery and exit of the substances involved in the metabolism of every cell of the tissues. In normal p h ysiological conditions, the optimal regulation of this process is accomplished t h rough the control of the state of tension of the smooth muscle cells present in t he vascular wall, which ultimately determines the maintenance of three different

homeostatic processes, namely the maintenance of fluid balance, the delivery of b lood to each microscopic domain of the tissues, and the maintenance of the syste m ic blood pressure. In normal conditions, the controls of the homeostatic processes act in concer t, causing the simultaneous adjustment of all variables in such a fashion that l o cal blood pressure, flow, and fluid balance are, on the average, kept within the

narrow range characteristic and necessary for the successful long-term survival o f the organism. The control of the state of smooth muscle constriction, or tone, is provided by three fundamentally different mechanisms, namely the numerous chemicals prese n t in the blood stream, the regulatory activity of the nervous system, and the sp e cial characteristic of these [smooth muscle] cells to react to changes in pressu r e, termed myogenic property. It is important to note that when the smooth muscle

ceases to be active-as a consequence of diseases, or because it has reached an e x treme limiting condition of constriction and dilation-flow, pressure, and exchan g e become regulated solely by the fluid mechanical characteristics of the microva s culature. This somewhat obtuse description focuses on the concern that the microvascula ture (i.e., capillaries) can become constricted and unresponsive to vasodilation

signals, thus limiting their ability to regulate blood flow. In the absence of r e gulation, especially when there are constricted vessels that do not allow the op t imal flow of blood, the surrounding tissues can become damaged. From the traditi o nal Chinese perspective, the authors are describing a syndrome of blood stasis t h at is secondary to a disorder of the qi circulation, particularly of the weiqi, w hich is responsible for regulating the vessel walls (the yingqi carries the subs t ances that can induce changes in the vascular walls, such as the vasodilation si g nals these authors mentioned). One of the therapeutic substances of great interest in relation to microcircu lation was an alkaloid that had been recently isolated: anisodamine (from Anisod u s tanguticus, an herb found primarily in the Tibetan region). This compound was i ntroduced into clinical use in China as a synthetic drug in 1965, initially for t reatment of epidemic meningitis, a problem that was causing widespread disabilit y and deaths. Later, anisodamine was shown to produce favorable results in treatm e nt of numerous serious ailments, including shock, glomerular nephritis, rheumato i d arthritis, hemorrhagic necrotic enteritis, eclampsia, and lung edema. The mech a nism of its actions were sought and traced to a vasodilating action that affecte d the microcirculation (9, 10). Unfortunately, potent alkaloid drugs can be dangerous, and anisodamine fell i nto the category of a drug therapy requiring careful monitoring (the whole herb a lso contains the alkaloids hyoscyamine, anisodine, scopalamine, and cuscohygrine , all potentially toxic). Adverse effects of the whole herb include dry mouth, di z ziness, headache, blurred vision, lassitude, drowsiness, palpitation, and dysuri a ; the isolated anisodamine has fewer side effects, but may still cause these sym p toms (11). The main method of administration of anisodamine in Chinese hospitals

was by injection, using just 50 mg or less, a relatively tiny amount. The interest in microcirculation that was spurred by the use of anisodamine t urned out to have positive implications for salvia. At the same conference, Dr. A . Koo, from the Department of Physiology at the Chinese University of Hong Kong,

described widely used Chinese herbs that had good potential for treating microci r culation disorders by their vasodilation activity: salvia, ilex (maodongqing), a n d capillaris (yinchenhao). Dr. Koo described the nature and importance of microc i rculation, reflecting the description by Xiu and Intaglietta, but mentioning the

specific vessels explicitly (12): Microcirculation has been demonstrated as occupying a key position in the car diovascular system. Thus, in classical description, structural components of a m i crovascular bed include a network of microvessels and terminal capillaries. Amon g several types of microvessels, terminal arterioles (20-50 micrometers in diamet e r) are distinctly different from others by the presence of a profusely reactive c ircumferential layer of vascular smooth muscle cells. The function of arterioles

in the circulatory system is indeed the myogenic reactivity of these vascular sm o oth muscle cells. Hence, active changes in dimension of arterioles not only regu l ate local blood flow to downstream capillaries supplying organs and tissues, but

also alter total peripheral resistance to flow as well as control systemic arter i al pressure. Usually, two types of myogenic activities of arterioles are observe d : sustained constriction or dilation, and rhythmic alterations of contraction an d relaxation (vasomotion). Such sustained or rhythmic myogenic activities are eit h er responses of vascular smooth muscle to endogenous neural and humoral effects,

or induced by exogenously administered drugs, including vasoactive agents from C h inese medicinal herbs. The implications for medical research and application seemed very promising, so a search through the range of Chinese herbs for active constituents that are v asoactive-and that specifically effect microcirculation-was undertaken. This tim e , the emphasis was on herbs of low toxicity that would allow widespread and regu l ar use. To observe the effects of herb components on the small vessels, Koo developed a video microscope (first reported by him in 1977), which he used in laboratory

animal studies to view internal tissues (exposed by surgery). The development of

laser technology around that time permitted improved observation of blood pulsin g through the microvessels, by utilizing on a doppler flowmetric technique (in es s ence, observing light reflected from a moving object to determine its speed). Th i s procedure worked well for laboratory animal studies, but in order to move on t o clinical evaluations, it was necessary to examine the blood flow non-surgically .

A clinical microscopic viewing technique was developed in mainland China, fir st reported in 1979, in which circulation in burned skin was evaluated so as to m onitor the healing effects of herbal therapies (13). It was found that blood clo t s (thrombosis) within the capillaries in the area of burn damage led to necrosis

of the underlying skin; vasoconstriction and slow blood flow were the key condit i ons leading to thrombosis. Therefore, if a substance could counter vasoconstrict i on and, thereby, free up the blood flow, the level of necrosis could be lower, s o long as it was administered (internally or topically) very soon after the burn.

A traditional burn remedy, huzhang (Polygonum cuspidatum), was confirmed by this

method to be a useful agent that prevents thrombosis. It is still relied on for t his purpose today.

The same basic observation technique was applied to examination of capillarie s in the finger nail beds (see Figure 2). The nail bed is easy to view and is ri c hly endowed with capillaries very close to the skin surface beneath the nail. It

was theorized that the condition of the capillaries at this site would reflect t h e condition of the capillaries elsewhere in the body. One of the first applicati o ns of the nail bed measurements was reported at the Hong Kong conference (14). A

group of researchers at the Huashan Hospital of the Shanghai First Medical Colle g e reported that nail bed circulation in patients with chronic viral hepatitis wa s abnormal, and that as treatment of hepatitis with Chinese herbs progressed, wit h reduction of symptoms and liver inflammation, the nail bed circulation improved . Salvia was a featured herb in the treatment for hepatitis in these studies. The

authors concluded their presentation thus:

Figure 2: Images of nail bed capillaries before and after treatment with salvia.

Salvia has been tried clinically in our hospital. The results suggest that pr omoting blood circulation will be beneficial to microcirculatory perfusion, hast e n the development of collateral circulation, and lower the lactic acid content w i thin the microcirculation. With the improvement in microcirculation, deficiency o f blood and anoxia in liver tissues could be relieved, these in turn will be ben e ficial to the recovery and regeneration of liver cells. Repeated liver biopsies h ad been done in 5 patients, 3 of them were treated with medicines activating blo o d circulation and eliminating blood stasis. Pathologic findings were improved, b u t not completely recovered in 2 cases. Their microcirculation was also improved.

Thus, the use of blood activating and sludge eliminating medicines is worth stud y ing. These findings led to widespread use of microscopic studies of nail bed circu lation and intensive use of salvia for treatment of conditions thought to be ass o ciated with microcirculation disorders, especially hepatitis, a disease that aff e cts many millions of Chinese. In the same year as the Hong Kong conference, the J ournal of Traditional Chinese Medicine (English language version) offered its fi r st report on microcirculation: it involved use of salvia for the prevention and t reatment of experimental cirrhosis (15). The authors, working at the Laboratory o f Hepatic Diseases at the Shanxi Medical College, pointed out that salvia was al ready being widely used in China for treatment of chronic liver disease. Some of the substances used for treating hepatitis (e.g., glycyrrhizin from licorice and oleanolic acid from ligustrum) previously tested by the authors, showed good resu lts in inhibiting liver damage due to fibrosis, but did not have an effect on exi sting fibrosis. The findings with salvia indicated that, after three weeks treatm ent of laboratory animals with induced liver damage, the fibrous septa were thinn er or disappeared. The authors wrote: Cirrhosis is characterized by connective tissue septa and hyperplastic liver nodules. The excess fibrous tissue between the hepatic nodules result from the c ollapse of the existing fibrous frame after necrosis of the liver cells. Fibrosis is therefore the consequence of liver cell necrosis....In our experiments, we ob served that the disturbances of hepatic microcirculation affected metabolic excha nge between the blood and the liver cells resulting in degeneration [necrosis] of the liver cells. The vicious cycle of necrosis-fibrosis-necrosis thus aggravated cirrhosis of the liver. Salvia treatment reduces these pathological changes, spe eds blood circulation, and opens up a larger capillary network. Microcirculation of the liver is thus improved by salvia, breaking the vicious cycle and preventin g occurrence of cirrhosis. Nearly 20 years later, salvia has become the main herb recommended for preven tion and treatment of liver damage due to viral hepatitis (see: Hepatitis C: upd ate 2001). The mechanism of action of salvia on preventing fibrosis in the liver has been tentatively elucidated. Fibrous collagens are released by hepatic stella te cells (fat storage cells) that have been activated and transformed into myofib roblasts rich in alpha-actin. This transformation occurs when the cells are expos ed to activators such as hepatic viral infection, excess iron or alcohol, liver-d amaging drugs, tumor invasion of the liver, or excess bile due to cholestasis. Th e myofibroblasts are then responsible for excess collagen deposition resulting in fibrosis and cirrhosis of the liver. As described in one laboratory animal study (26): "The extract of Salvia miltiorrhiza markedly reduced protein expression of alpha-smooth muscle cell-like actin, which indicates that hepatic stellate cell activation was inhibited during liver fibrosis." The inhibition of hepatic stella te cell activation was also suggested to be the mechanism of salvia action found in an in vitro study (27). The vasodilating activity of salvia may relax the stel late cells (actin is one of the components that contracts the stellate cells) and aid bile flow and hepatic blood circulation. Spontaneous resolution of liver fibrosis occurs mainly as the result of the a ction of collagenases, known as matrix metalloproteinases (enzymes incorporating heavy metals; these are partly induced by zinc), that breakdown the accumulated collagen. When new liver fibrosis is inhibited by salvia, it is possible that nat ural processes slowly reverse the existing fibrosis. Although not yet studied, it is also possible that salvia helps induce collagenase or reduces collagenase inh ibitors so that fibrosis recovery is speeded up. It has been proposed that liver regeneration is promoted by salvia through general mechanisms of improving hepati c microcirculation, reducing lipid peroxidation, elevating plasma levels of fibro nectin (an antifibrotic agent), and regulating immune responses (28). While treatment of angina and hepatitis remain the most common clinical appli cations of salvia in modern Chinese clinical practice, the herb has been shown t o have other valuable applications, based on its effects on microcirculation. For example, laboratory experiments with bone fracture healing at the Shanghai Insti tute of Traumatology and Orthopedics have indicated that salvia helps mobilize ca lcium and aid deposition of calcium to the fracture zone (16).

Active Constituents: The main active constituents of salvia are diterpene quinones, known as tansh inones (the Wade-Giles transliteration of danshen is tan-shen, hence the quinone s were called tanshinones). Most of these compounds are colored, providing the re ddish appearance of the roots. The group of components, labeled tanshinone I, tan shinone II, cryptotanshinone, etc. (see Figure 3), were first described by Japane se researchers in 1968 (17), though investigations had been underway since the pi gments were isolated from salvia in 1934 (18). More recently, nearly 40 variants of the basic tanshinone structures have been found in the roots. The tanshinones are unique chemical constituents, and similar compounds are not found in other Ch inese herbs. The total tanshinone content of the roots is about 1%, with tanshino ne I and II and cryptotanshinone being present in the largest amount (19). In one recent study, the extraction of salvia yielded tanshinone II 0.29%; cryptotanshi none 0.23%; tanshinone I: 0.11% (24). The isolated tanshinones have been shown to inhibit bacteria, reduce fever and inflammation, inhibit platelet aggregation, d ilate the blood vessels, and aid urinary excretion of toxins (22).

Figure 3: The primary active constituents of salvia.

Dosage, Toxicity,And Adverse Effects The Pharmacopoeia of the People's Republic of China (20) indicates a recommen ded dosage of 9-15 grams per daily dose in decoction form. In a few instances, h igher doses are administered, up to 20 grams per day, in the treatment of inflamm atory diseases, including viral hepatitis. According to English-Chinese Rare Chin ese Materia Medica, up to 30-60 grams can be used in cases of angina and heat-typ e arthritis (21). The relatively high dosage of salvia, compared to most other Ch inese herbs (typical dosage recommendations are 3-9 grams for many herbs) may be attributed to the relatively low level of active constituents and their poor solu bility in water. At the higher dosage levels, salvia may on rare occasions cause dry mouth, di zziness, lassitude, numbness, shortness of breath, and other symptoms that will usually disappear spontaneously without interrupting the treatment. Rare Chinese Materia Medica notes that salvia is not suitable for patients who have deficiency but not stasis, or deficiency accompanied by cold, or with tendency to bleed. Ho wever, most materia medica guides do not present these cautions. Salvia has very low acute toxicity, with an LD50 by injection of 40-80 g/kg (19). It is recommended that salvia, or its preparations used for treatment of poor blood circulation, not be combined with coumadin (Warfarin), as there is a poss ibility of increasing the anticoagulant effects (see: The interactions of herbs a nd drugs). In a literature survey conducted through October 2000, three cases of increased anticoagulant activity were reported in the literature in persons takin g salvia along with Warfarin (25). Such effects may be rare and are likely to be dose dependent, as the mechanism appears to be a simple additive effect of antico agulant activity of salvia along with that produced by Warfarin. Therefore, perso ns using coumadin should either avoid using salvia, or use it in relatively low d osage (not more than the equivalent of 6-9 grams per day in decoction) while payi ng attention to blood coagulation tests that are routinely performed for persons taking the drug.

Tanshine IIA isolated from Salvia miltiorrhiza BUNGE induced apoptosis in HL6 0 human premyelocytic leukemia cell line.

1. Abstract Apoptosis is a new therapeutic target of cancer research. Tanshinone IIA isol ated from Salvia miltiorrhiza BUNGE, a traditional oriental medical herb, was ob served to induce apoptosis in HL60 human premyelocytic leukemia cell line. Tanshi none IIA induced DNA fragmentation into the multiples of 180 bp and increased the percentage of hypodiploid cells in flow cytometry after propidium iodide (PI) st aining. Tanshinone IIA-induced apoptosis is accompanied by the specific proteolyt ic cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of caspase-3 , a major component in apoptotic cell death mechanism.

2. Introduction Apoptosis is cellular suicide or programmed cell death which is mediated by t he activation of an evolutionary conserved intracellular pathway. Recently the r elation of apoptosis and cancer has been emphasized and increasing evidence sugge sts that the processes of neoplastic transformation, progression and metastasis i nvolve alteration of normal apoptotic pathways. Apoptosis also gives some clues a bout effective anticancer therapy, and many chemotherapeutic agents were reported to exert their anti-tumor effects by inducing apoptosis of cancer cells.

Salvia miltiorrhiza BUNGE is a traditional oriental medical herb which belong s to the family of Labiatae, and has been used for treatment of coronary heart d isease, particularly angina pectoris and myocardial infarction. According to seve ral phytochemical reports, major constituents of the root of Salvia miltiorrhiza BUNGE are composed of phenolics such as lithospermate B and diterpene quinone pig ments such as tanshinones. Medical researchers have studied on the effect of magn esium lithospermate B on renal failure, and diterpene quinones have been reported for anti-platelet aggregation effect. Recently, it was found the growth inhibito ry effects of various tanshinones on five tumor cell lines, and it was shown that HCTIS/CL02, a multidrug-resistant tumor cell line, did not exhibit resistance to tanshinones even though it has resistance to doxorubicin. In this study, apoptosis-inducing effect of tanshinone IIA which is most abun dant and structurally representative among the tanshinones of Salvia miltiorrhiz a BUNGE was investigated in HL60 human premyelocytic leukemia cell line.

3. Results and Discusssion Recently, the anti-tumour effect of tanshinones isolated from Salvia miltiorr hiza BUNGE was elucidated using human tumour cell lines. Since many anticancer d rugs induce apoptosis of tumour cells, the apoptosis-inducing activity of the cru de extract of Salvia miltiorrhiza BUNGE was investigated. Human premyelocytic leu kemia cell line, HL60, was treated with various concentrations of the ether extra ct of Salvia miltiorrhiza BUNGE for 4 h, and it was found that it induced internu cleosomal DNA fragmentation, one of the biochemical hall mark of apoptosis, at th e concentration above 10 μg/ml. UV radiation was used as a positive control for the induction of apoptosis. Among the constituents of Salvia miltiorrhiza BUNGE, tanshinone IIA was focused on, because it is most abundant and structurally repre sentative having a basic tanshinone skeleton. Using a similar phytochemical proce dure with the previous report, tanshinone IIA was successfully purified and the s tructure of it was clearly identified compared with the previous report. When HL6 0 cells were treated with various concentrations of tanshinone IIA, internucleoso mal DNA fragmentation was induced by the concentrations as low as 1 μg/ml. In ti me course experiment in which 3 μg/ml of tanshinone IIA was treated, 180 bp ladd er was generated at 2 or 3 hours after the treatment. Microscopic observation sho wed that the crude ether extract of Salvia miltiorrhiza BUNGE and purified tanshi none IIA both induced cellular morphological changes characteristic of apoptosis including membrane blebbing and apoptotic body formation. Flow cytometry analysis of tanshinone IIA-treated HL60 cells showed the increase of hypodiploid apoptoti c cells and the decrease of the cells at G1 phase of cell cycle, suggesting a pos sibility that tanshinone IIA induced apoptosis occurs at G1 phase of cell cycle. PARP is a nuclear enzyme which is involved in DNA repair process, and recently, i t was found that 113 kDa PARP protein is cleaved into 89 and 24 kDa fragments by the action of CPP32, a protease recently named as caspase-3. Since the specific proteolytic cleavage of PARP is considered to be a biochem ical characteristic of apoptosis, the Western blotting experiment was carried ou t using the antibody against PARP. The results demonstarted that PARP is cleaved into 89 kDa fragment 4 hours after the addition of tanshinone IIA suggesting that caspase-3 was activated. To measure the caspase-3 activity directly and quantita tively, Ac-DEVD-pNA was used, a specific colorimetric substrate of caspase-3. The results demonstrated that caspase-3 is activated during tanshinone IIA-induced a poptotic process. Recently, many papers reported that internucleosomal DNA fragme ntation is not essential in apoptotic cell death, and some necrotic cell death is accompanied by internucleosomal DNA fragmentation, suggesting the possibility th at internucleosomal DNA fragmentation may be not enough as an indicator of apopto tic cell death. It is, however, clear that the central mechanism of apoptosis is evolutionary conserved and caspase activation is an essential step in this comple x apoptotic pathways. The results of the study, therefore, give more important ev idences that tanshinone IIA-induced cell death is apoptosis. In this study the apoptosis inducing activity of tanshinone IIA, a main ingre dient of Salvia miltiorrhiza BUNGE, was examined. Other tanshinone components st ructurally related to tanshinone IIA such as cryptotanshinone and tanshinone I al so exist in the root of Salvia miltiorrhiza BUNGE, and the apoptosis-inducing act ivity of other tanshinones will be examined later especially focusing on caspase activity which is central component of apoptotic pathway.

[Amanuensis&Symbol trace Calligrapher: Michael Derrida]

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What is danshen?Inhibition of mast cell degranulation by tanshinones from the roo

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