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Modern Ayurveda

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Hederacine A Hederacine B

Qlechoma brevituba Kuprian. is a stoloniferous, perennial, prostrate herb that grows in China. The leaves are simple, decussate and exstipulate. The petioles are long. The base of the blade is cordate. The flowers are tubular, dilated at apex, and bilobed. The fruits are dark brown, oblong-ovoid, smooth or impressed-punctuate, and glabrous. The plant is used in China to reduce fever, promote urination and the heart tone, and to cure colds and gravel. The pharmacological potential of Glechoma brevituba Kuprian. remains unexplored. An interesting feature of the Glechoma species is their ability to elaborate long-chain unsaturated fatty acids with anti-inflammatory, analgesic, antipyretic potentials. One such fatty acid is (9S,10E,12Z)-9-hydroxy-10,12-octadecadienoic acid, an antagonist of PGs E1 and D2 (27,28). Note also the the presence in the Glechoma species of a very unusual series of alkaloids (29), the structural features of which has some similarity to rofecoxib. Therefore, it would be interesting to learn whether these alkaloids hold any potential as a COX inhibitor or not.

INHIBITORS OF LIPOXYGENASES

Lipoxygenases are present in leukocytes, tracheal cells, keratinocytes, and airway and stomach epithelium, and they catalyze the introduction of a molecule of oxygen to the 5-position of arachidonic acid to give the intermediate (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoic acid or 5-HETE, which is immediately followed by the rearrangement of 5-HETE to leukotrienes. Another potential site of action for anti-inflammatory drugs is, therefore, at the level of lipoxygenases, thus inhibiting the biogenesis of leukotriene and 5-HETE. The search for specific inhibitors of lipoxygenase activity from medicinal plants results in the characterization of anti-inflammatory agents. Lipoxygenase inhibitors might hold some potential for the treatment of asthma, psoriasis, arthritis, allergic rhinitis, cancer, osteoporosis, and atherosclerosis. The evidence currently available suggests the families Myrsinaceae, Clusiaceae, and Asteraceae have potential as sources of lipoxygenase inhibitors.

Medicinal Myrsinaceae

The family Myrsinaceae consists of 30 genera and about a 1000 species of tropical plants that have attracted a great deal of interest for their quinones and saponins, which have exhibited a large spectrum of pharmacological activities. About 40 species of plants classified within the family Myrsinaceae are medicinal in the Asia-Pacific region, particularly for the treatment of inflammatory conditions. One of these medicinal herbs is Ardisia villosa Roxb. Ardisia villosa Roxb., or xue xia hong (Chinese), is a shrub that grows up to 3 m tall in the wild in China, Taiwan, Thailand, and Malaysia. The stems are stoloniferous, blackish, rusty villous, or hirsute almost throughout. The leaves are simple, spiral, and exstipulate. The blade is selliptic-lanceolate, somehow fleshy, light green, and marked with numerous blackih dots. The flowers are lavender or pink. The fruits are dark red or blackish with globose berries (Fig. 16). The plant is used in China to treat contusions and rheumatic and neuralgic pains. In Malaysia, a decoction of leaves is used as bath to treat dropsy; the roots are used to reduce fever and treat cough. An interesting feature of Ardisia species, and the Myrsinaceae family in general, is the production of a very unusual series of dimeric benzo-quinones known as ardisiaquinones, which are known to inhibit the enzymatic activity of 5-lipoxygenases, a feature that could explain the frequent use of Ardisia species to treat inflammatory conditions. One such compound is ardisiaquinone G isolated from Ardisia teysmanniana, which is known to inhibit the enzymatic activity of lipoxygenase (30,31).

Hyperforin Perforatum

Ardisiaquinone G

Medicinal Clusiaceae

Hyperforin, the major constituent in Hypericum perforatum (St. John's Wort), inhibits the enzymatic activity of 5-lipoxygenase and COX-1 in platelets, acts as a dual inhibitor of 5-lipoxygenase and COX-1, and might have some potential in inflammatory and allergic diseases connected to eicosanoids (32). Several Hypericum species are of medicinal value in Asia and the Pacific. One of these is Hypericum erectum Thunb., the potential of which as a source of 5-lipoxygenase is given here.

Hyperforin Perforatum
Fig. 17. Hypericum erectum Thunb.

Hyperforin

Hypericum erectum Thunb., or otogirisou (Japanese), is an herb of grassy places and thin woods in the hills and mountains of Japan, Korea, and China. The plant is a lithe herb with decussate leaves and yellow flowers (Fig. 17). In Japan, the juice expressed from the leaves is used to heal cuts and sooth bruises. A decoction of the fruits is used to stop bleeding. In Vietnam and Cambodia, a paste of the aerial parts is applied to dog bites and bee stings, and is used internally for the treatment of malarial fever. Hypericum erectum Thunb. is an important herb in Chinese medicine as an anti-hemorrhagic agent, astringent, and antibiotic that is known to contain antiviral phloroglucinol derivatives, as well as the anti-hemorrhagic compounds otogirin and otogirone. Also, because the plant is known to elaborate a series of polyprenylated phloroglucinol derivatives including erectquione A, B, C, its potential as a lipoxygenase inhibitor would be worth assessing (33).

Erectquione A

Medicinal Asteraceae

One of the richest sources of lipoxygenase inhibitors is perhaps the family Asteraceae, where three different types of principles have been characterized. The sesquiterpene lactone helenalin, which can be isolated from several plant species of the Asteraceae family, is a potent anti-inflammatory and antineoplastic agent. In human granulocyte, helenalin inhibited 5-lipoxygenase (IC50 9 mM after 60 min preincubation) in a concentration- and time-dependent fashion (34). Polyacetylenes from Artemisia monosperma showed some levels of activity against lipoxygenase (35). The third group of lipoxygenase inhibitors in this family are bornyl cinnamoyl derivatives from Verbenisa species, such as bornyl caffeate from the South American herb Verbenisa turbacensis Kunth.

ch2oh

Polyacetylene

The family Apiaceae is a large group of flowering plants which comprises some 250 genera of herbs, mostly growing in temperate regions, the principal botanical hallmark of which is the presence of umbels, dissected leaves, pungent or aromatic smell, and hollowed and articulate stems. A large number of Apiaceae is of value in Western medicine, notably Anethum graveolens L. (dill, British Pharmaceutical Codex, 1954), Foeniculum vulgare (fennel, British Pharmaceutical Codex, 1963), Apium graveolens L. (celery, British Pharmaceutical Codex, 1949), Carum carvi L. (caraway, British Pharmacopoeia, 1963), Coriandrum sativum L. (coriander, British Pharmacopoeia, 1963), and Pimpinella anisum (anise, British Pharmaceutical Codex, 1954). A number of plants classified in this family are drastically toxic on account of coniine, such as Conium maculatum L. (hemlock leaf, British Pharmaceutical Codex, 1949).

(-)-Bornyl caffeate

The traditional system of medicine of the Pacific Rim uses approx 80 species of Apiaceae, for instance, Centella asiatica (L.) Urban (Hydrocotyle asiatica L.; centella, Indian Pharmaceutical Codex, 1955). The plant has been used in India since early times for skin diseases and as a diuretic. It has long been a popular remedy in India for leprosy and syphilis. However, large doses are said to have narcotic action. The plant was used also by the surgeons of Napoleon's army.

Bupleurum chinense DC (Bupleurum falcatum L. var scorzoneraefolium (Willd.) Ledeb, Bupleurum octoradiatum Bge. Bupleurum chinense Franch, Bupleurum chinense f. vanheur-ckii (Muel.- Arg) R. H. Shan & Yin Li, Bupleurum falcatum f. ensifolium H. Wolff, Bupleurum togasii Kitagawa, Bupleurum vanheurckii Muel- Arg ), or bei chai hu, tz' u hu, ch'ai hu (Chinese), is a perennial herb that grows to a height of 90 cm in China, Mongolia, India, Korea, and Taiwan from a stout elongate, brown, and woody root.

Medicinal Apiaceae

Bupleurum Chinense
Fig. 18. Bupleurum chínense DC.

The leaves are simple, spiral and 4-7 cm X 5-8 mm. The blades of basal leaves are ellipticat and the cauline ones are linear-lanceolate. The inflorescence consists of numerous umbels spreading to form a large, loose panicle. The flowers are bright yellow. The achenes are oblong, brown, and prominently ribbed (Fig. 18). In Asia, this plant is valued as a remedy for fever, rheumatism, gout, and inflammatory illnesses. In China, the roots are used as febrifuges, deobstruents, and carminatives, and are used to assuage muscle pains, thoracic and abdominal inflammations, puerperal fever, and diarrhea.

A significant advance in the understanding of the anti-inflammatory properties of Bupleurum fruticescens has been provided by Prieto et al. (36). The showed that a methanol extract from the aerial parts had a significant effect on 5-lipoxygenase activity, inhibiting both LTB4 and 5(S)-HETE production, with IC50 values of 112 and 95 pg/mL, respectively. At concentrations of 200 pg/mL, the extract inhibited COX-1 (90%) and elastase activities (54%). What are the principles involved here, saponin?

INHIBITORS OF ELASTASE

The seeds and vegetative part of plants contain several sorts of inhibitors of insect, fungal, mammalian, and endogenous proteinases. These inhibitors may be involved in plant defense mechanisms against predators and participate in the development of the plant itself. Peptidic proteinase inhibitors are well studied in the families Fabaceae, Poaceae, Asteraceae, and Solanaceae (37). Non-proteinaceous inhibitors of serine protease are, in comparison, less known. Among serine proteinases are human neutrophils and macrophages, which digest degrade elastin, cartilage proteoglycans, fibronectin, and foreign materials ingested during phagocytosis.

In normal physiological conditions, it is inhibited by a-1-protease inhibitor of plasma. Damage to connective caused by leakage of elastases leads to damage associated with inflammatory diseases, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, carcinogenesis, chronic bronchitis, and rheumatoid arthritis. Compounds that directly inhibit elastase or its release from human neutrophils are of enormous pharmaceutical and cosmetological interest in the development of new anti-inflammatory drugs. A possible source for elastase inhibitors are the medicinal Asteraceae and Droseraceae, particularly those used as traditional medicine in Asia.

Medicinal Asteraceae

The family Asteraceae is a prolific source of sesquiter-pene lactones, among which, melampolides have been shown to inhibit the enzymatic activity of elastases. Melampolides are a common member of the Melampodi-inae subtribe. Examples of medicinal Asteraceae known to elaborate melampolides are Sigesbeckia orientalis L. and Mikania cordata (Burm.f.) B.L. Robinson.

Sigesbeckia orientalis L., or sigesbeckia, commonly known as St. Paul's wort, sa phaan kon (Thai), hi lien, chu kao mu, hu kao, kou kao, and nien hu ts'ai (Chinese), is an annual, branched herb that grows up to 1.2 m tall in Asia and the Pacific Islands. The capitula are bright yellow (Fig. 19). The plant has the reputation of "smelling like a pig" in China, where it is used to treat fever, snake bites, skin diseases, loss of appetite, chronic malaria, numbness of the extremities, and cancerous sores. In Taiwan, the plant is used to reduce swellings. In the Philippines, a decoction of the plant is used to heal wounds. A patent showed the ability of the plant to stimulate wound healing, to promote healing, and to restore elasticity to damaged skin. The dermis is thick, supple, and sturdy layer of connective tissue that encompasses a dense meshwork of collagen and elastin fibers, which are responsible for elasticity, tone, and texture. When the coils of collagen and elastin suffer cuts and crosslinking damage and the skin losses much of its strength and elasticity, wrinkles appear. This initial research led to an investigation of Sigesbeckia orientalis L.'s ability to restore normal quantities of collagen and elastin fibers in abnormal stretching of the dermis (pregnancy, change in weight) from a linear scar or from some endocrine disorders. Are melanpolides involved here? (38,39; Fig. 20).

Sigesbeckia glabrescens Mak., or hi chum (Korean; Fig. 21), is used in Korea to treat liver and kidney diseases, asthma, allergic disorders, costiveness, deafness, and blindness. In China, the plant is prescribed for rheumatic pain, numbness, weak bones, and to wash boils. The anti-inflammatory property of Sigesbeckia glabrescens Mak. is

Sigesbeckia Orientalis
Fig. 19. Sigesbeckia orientalis.

confirmed experimentally, as an intraperitoneal injection of an aqueous extract of the plant inhibited compound 48/80 induced systemic anaphylaxis in mice. The extract dose-dependently inhibited the release of histamine from peritoneal mast cells by compound 48/80. The plant has a strong antianaphylactic activity by inhibition of histamine release from mast cells (40). The extract dose-dependently inhibited the active systemic anaphylaxis and serum IgE production induced by immunization with ovalbumin and interleukin (IL)-4-dependent IgE production by lipopolysaccharide (LPS)-stimulated murine whole spleen cells (41). Note that serine protease enzymes induces the release of significant amounts of histamine from mast cells, and that the anti-histaminic effect described earlier could result from a possible inhibition of elastase by melampolides, but this remains to be confirmed (42).

Note that darutoside, a diterpene including isolated from Siegesbeckia glabrescens Mak. abrogated early pregnancies in experimental rats at a dosage of 20-40 mg/kg (43). Mikania cordata (Burm.f.) B.L. Robinson (Mickania scandens [L.] Willd, Eupatorium caudatum Burm.f, Eupatoirum volubile Vahl, Mikania volubilis [Vahl] Willd, Mikania chenopodifolia Willd), or river vine, heartleaf hem vine, or climbing hemp vine, is a climber native to tropical America. The plant grows throughout Southeast Asia to the

Fig. 21. Sigesbeckia glabrescens Mak.
Siegesbeckia Glabrescens

Bismarck Archipelago. The leaves are cordate, and the capitula are grouped in panicles (Fig. 22). In Taiwan, the plant is used to resolve swellings. In Malaysia, it is used to calm itches, and in Indonesia it is used to heal wounds.

Mikanolide

Deoxymikanolide

Mikania cordata is known to elaborate a series of sesquiterpene lactones, among which deoxymikanolide significantly inhibits acetic acid-induced writhing in mice (44,45). The plant also contains a series of melampolides that inhibit the enzymatic activity of elastase (46).

Medicinal Droseraceae

The family Droseraceae consists of four genera and about 100 species of perennial herbs, of which Drosera burmannii Vahl, Drosera rotundifolia L, Drosera indica L., and Drosera peltata Sm. are used in Asia for the treatment of cough. Naphthoquinones and flavonoids, which occur in this family, have not been fully studied for pharmacology, and it appears that flavonoids inhibit human neutrophil elastase, hence the potential for the treatment of inflammation.

Drosera rotundifolia L., or round leaf sundew, is a little perennial herb that can reach 35 cm in height. The plant is found in temperate bogs and swampy areas. The leaves are simple, fleshy, broadly ovate and arranged into rosettes. The leaves are covered with sticky, shiney, red tentacles. The flowers are pink (Fig. 23).

Fig. 23. Drosera rotundifolia L.

The plant has been traditionally used in Europe to treat chronic bronchitis, asthma, and whooping cough, and the entire air-dried plant, or Drosera, was listed in the French Pharmacopoeia in 1965 (tincture, 1 in 5; dose 0.5-2 mL), and in 1880, Murray described its uses in the Royal Hospital for whooping cough. In Japan, a decoction of the plant is used to treat cough. This effect is probably mediated by flavonoids such as hyperoside, quercetin, and isoquercitrin, which are known to abound in the plant (47). Quercetin from Drosera madagascariensis inhibits human neutrophil elastase with an IC50 value of 0.8 (xg/mL, as well as hyperoside (IC50 0.15 (xg/mL) and isoquercitrin (IC50 0.7 (xg/mL [48]).

OH O

Quercetin

INHIBITORS OF NITRIC OXIDE SYNTHETASE

NOS is an important enzyme involved in the regulation of inflammation, vascular tone, neurotransmission, and cancer. NO is generated via oxidation of the terminal guanidine nitrogen atom from L-arginine by NOS. NO is a very toxic free radical that can cause substantial tissue damage in high concentrations, especially in the brain. In stroke, for example, large amounts of NO are released from nerve cells to cause damage to surrounding tissues including neurones and myocytes. NO is also released during inflammation and is involved in the growth of tumors; it is understood that endo-genously formed NO induces the malignant transformation of mouse fibroblasts. Among NOSs, inducible NOS is involved in the overproduction of NO and is expressed in response to IL-1p, tumor necrosis factor-a, and LPS, the genetic expression of which is notably commanded by the NF-kB macrophages. Molecules capable of inhibiting inducible NOS and/or induction of NF-kB activation may be of therapeutic benefit in various types of inflammation. Such molecules could be of sesquiterpenic nature as discussed under the following subeadings.

Medicinal Asteraceae

There is an expanding body of evidence to suggest that sesquiterpene lactones inhibit the synthesis NO synthetase. One such compound is an ambrosanolides-type sesquiter-pene known as cumanin characterized from Ambrosia psilostachya. This sesquiterpene inhibit the enzymatic activity of NO synthetase with an IC50 value of 9.38 ^M (49). Another example is the well-known artemisinin, a sesqui-terpene used as an alternative drug in the treatment of severe and multidrug-resistant malaria, which inhibits NO synthesis in cytokine-stimulated human astrocytoma T67 cells (50).

Other sorts of NO inhibitors are triterpenes, such as ursolic acid and 2-a-hydroxy ursolic acid and 2-a-hydroxy ursolic acid from Prunella vulgaris L., inhibit the production of NO by murine leukaemic monocyte macrophage cells, RAW 264.7, cultured in vitro. The IC50 values were 17 (iM for ursolic acid and 27 (iM for 2-a-hydroxy ursolic (51).

Inula chinensis Rupr. ex Maxim. (Inula japonica Thunb., Inula britannica L.), or hsuan fu hua, is indigenous of northern China, Mongolia, Korea, and Japan (Fig. 24). It is a perennial herb that grows to a height of 60 cm. The drug consists of the flowers dried in the sun, are used in China as analgesic, to treat swellings, sore throat, cough, vomiting, fullness of chest and as a deobstruent and laxative, diuretic, depurative, tonic, and carminative. Hernandez et al. characterized from

Fig. 24. Inula chinensis Rupr. ex Maxim.

Inula viscosa a sesquiterpene lactone, inuviscolide, which reduces the phospholipase A2-induced edema with an inhibitory dose at which half of the phospholipase A2-induced edema was reduced, ID50, value of 98 mmol/kg (52). Han et al., studied the mechanism of action of 1-0-acetyl-4R,6S-britannilactone, a sesquiterpene isolated from the flowers of Inula britannica and showed that this substance suppressed NO and PGE2 synthesis in RAW 264.7 macrophages through the inhibition of iNOS and COX-2 gene expressionvia a blocking the binding of NF-kB to the promoter in the target genes (53,54). Other sesquiterpenes able to inhibit the enzymatic activity of inducible nitric oxide synthase from the genus Inula are bigelovin, 2,3-dihydro-aromaticin and ergolide, which potently inhibits the activity on LPS-induced NOS in murine macrophage RAW 264.7 cells with an IC50 value of 0.46 mM, 1.05 and 0.69 pM, respectively (55).

Cox Vegf InosDamp Macrophage
Fig. 25. Carpesium divaricatum Sieb. et Zucc.

Carpesium divaricatum Sieb. et Zucc., or gankubisou (Japanese), is an herb that grows to a height of 1 m in shady and damp waste places, roadsides, and hillsides in China, Japan, and Korea. The leaves are lanceolate, and the inflorescences consist of yellow, cylindrical capitula (Fig. 25).

2ß, 5-epoxy-5, 10-dihydroxy -6oc-angeloyloxy -9ß-isobutyloxy -germacran -8a, 12-olid

The plant has been used in traditional Korean herbal medicine for its antipyretic, analgesic, and anti-inflammatory properties vermifuge.

The active principle involved in the antipyretic, analgesic, and anti-inflammatory traditional uses is a sesquiterpene known as 2p,5-epoxy-5,10-dihydroxy-6a-angeloyl-oxy-9p-isobutyloxy-germacran-8a,12-olide. This sesquiterpene lowers the production of NO by LPS/IFN-7-stimulated RAW 264.7 cells in a concentration-dependent manner, with an IC50 value of approx 2.16 mM. This carence in NO is not owed to inhibition of the enzymatic activity. In addition, Kim et al., showed that the cells exposed to the sesquiterpene had lower level in iNOS protein and mRNA suggesting inhibition of nuclear factor-kappaB (NF-kappaB) activation through a mechanism involving the inhibition of iNOS gene expression via inhibition of NF-kB DNA binding (56,57).

Medicinal Lauraceae

The family Lauraceae consists of 50 genera and 2000 species of trees, shrubs, and herbs, of which 70 are of medicinal value in the Asia-Pacific region. Lauraceae are well-known for elaborating isoquinoline alkaloids and sesquiterpenes, the latter most likely representing a vast source of material for the search for NOS. Examples of such compounds are costunolide and dehydrocostunolide found in the leaves of Laurus nobilis (bay leaf, laurel), the leaves of which are widely used as a spice, antiseptic, stomachic, and to treat rheumatism in traditional European medicine (58). The potential of Neolitsea zeylanica Nees (Merr.) as a potential source of NOS inhibitor is discussed here.

Neolitsea zeylanica Nees (Merr.) (Tetradenia zeylanica Nees, Litsea zeylanica Nees) or shore laurel, tejur (Malay), Or nan ya xin mu jiang zi (Chinese), is a tree that grows up to 20 m tall in forests and thickets from sea level up to 1000 m in Burma, Malaysia, Sri Lanka, Borneo, the Philippines, India, China, and Australia. The young stems are glabrous. The leaves are simple, alternate, or crowded at apex of stems. The blades are ovate-oblong or oblong and glaucous beneath. The flowers are small and arranged in axillary, subsessile, four- to five-flowered umbels. The fruits are subglobose, 8 mm-1.5 cm in diameter, and seated on a disc-shaped, wavy, marginated perianth.

H2C

Dehydrocostus lactone

In Malaysia, a paste of the roots is applied to fingers to treat eruptions. The plant is known contain some sesquiterpene lactones including neolinderane, zeylanine, zey-lanicine and zeylanidine (59-61), the potential of which as an inhibitor of NOS would be worth investigation because pseudoneolinderane and linderalactone inhibited the production of superoxide anion generation by human neutrophils in response to fMLP/CB. The IC50 values for pseudoneolinderane and linderalactonewere 3.21 and 8.48 pg/mL, respectively (62).

pseudoneolinderane linderalactone

pseudoneolinderane linderalactone

Fig. 26. Litsea cubeba. Flora of Malay peninsula. Geographical localization: Bukiy Kutu, Kudla Kubu. Date: 12/25/1930. No 23848. Field collector: Cooman. Botanical identification: F.S.P. Ng, 11/27/2001.

Litsea cubeba (Lour.) Pers. (Litsea citrata Bl., Laurus cubeba Lour., Daphnidium cubeba), or pokok myuniak kayah puteh (Malay, Indonesian), is a shrub which grows wild in China, Korea, Vietnam, and Indonesia. The stems are smooth; the leaves are aromatic, simple, and exstipulate. The petiole is about 1 cm long. The blade is lanceolate, thinly coriaceous, 12-4 cm X 3-1 cm and shows six to eight pairs of secondary nerves. The fruits are globose and 3 mm in diameter (Fig. 26).

cis a-ocimene

3,7-dimethyl-1,6-octadien-3-ol

In China, the seeds are eaten to promote digestion and treat cough and bronchitis. In Vietnam, Cambodia, and Laos, a decoction of the plant is used to treat mental disorders such as hysteria and forgetfulness. In Taiwan, the plant is used to treat athlete's foot and other skin diseases.

The plant is strongly aromatic on account of an essential oil which comprises cis-a-ocimene (25.11%), 3,7-dimethyl-1,6-octadien-3-ol (16.85%), and trans-nerolidol (13.89%), hence the use of the plant in aromatherapy. A methanolic extract of bark of Litsea cubeba (Lour.) Pers. and its fractions (0.01 mg/mL) from bark inhibit NO and PGE2 production in LPS-activated RAW 264.7 macrophages without significant cytotoxicity at less than 0.01 mg/mL concentration. The methanol extract decreased the enzymatic activity of myeloperoxidase (0.05 mg/mL). These findings suggest that L. cubeba is beneficial for inflammatory conditions and may contain compound(s) with anti-inflammatory properties (63). Can we expect the vasorelaxant laurotetanine (64) isolated from the plant to exert such activity?

Laurotetanine

Litsea odorifera Val., or medang pawas (Indonesian), is a tree that grows in Indonesia and eastward to Papua New Guinea. The stem is slightly lenticelled. The leaves are simple, exstipulate, and glossy. The blade is broadly lanceolate, 7.5 X 5 cm, and shows four to five pairs of secondary nerves. The fruits are to 1 cm long, dark green with white spots, glossy, and ovoid (Fig. 27). The plant is used to treat biliousness, to promote lactation, and to heal boils and furuncles. The pharmacological potential of this plant is unexplored, and it would be interesting to know whether further study reveals evidence of nitric oxidase inhibition.

Medicinal Solanaceae

The family Solanaceae consists of about 85 genera and 2800 species of plants, of which, 80 are of medicinal value in the Asia-Pacific region. Solanaceaeare well known for their parasympatholytic tropane alkaloids, such as hyoscyamine. Classic examples are Atropa belladonna L. (belladona herb, British Pharmacopoeia 1963), Datura stramonium L. (stramonium, British Pharmacopoeia, 1963), and the dried leaves and flowering tops of Hyoscyamus

Coloriage Maternelle Pointiller
Fig. 27. Litsea odorifera Val. BOSWESEN. Nederlands New Guinea (Forestry Division Neth. New Guinea) Field collector: F. Schram No B 1737. Date: 3/9/1955. Geographical localization: New Guinea, Res. Manokawaii, Sidei, altitude: 7 m.

niger L. (hyoscyamus, British Pharmacopoeia, 1963), which have been used as antispasmodic drugs. In the family, the genus Physalis is known to produce 16,24-cyclo-13,14-secosteroidal terpenes called physalins, which might be of interest as inhibitors of NOS. An example of medicinal Physalis is Physalis alkekengi, a medicinal plant of the Asia-Pacific region.

Physalin F

Ghiocei Desen

Physalis alkekengi, or Chinese lantern, alkekengi, bladder cherry, ground cherry, strawberry tomato, winter cherry, suan chiang, or teng leng ts'ao, is an ornamental perennial herb that grows to a height of 80 cm in Eurasia. The leaf blade is narrowly to broadly ovate. The flowers are mostly white, with a greenish or yellowish eye, and are rotate or campanulate. The fruits are shiny, orange-red, globose, 1-1.5 cm in diameter. The berries are enclosed in an inflated calyx that resembles a little lantern (Figs. 28 and 29). The plant is used in China to break fever, promote urination, and treat cough. The seeds are used to promote labor. Physalis alkekengi is known to elaborate a series of 16,24-cyclo-13,14-secosteroidals known as physalins, such as physalins N and O. Physalins B, F, and G from Physalis angulata L. lower NO, tumor necrosis factor-a, IL-6, and IL-12 release by macrophages stimulated with LPS and IFN-7 (65). It would be interesting to learn whether further studies on Solanaceae, and Physalis species in general, disclose any molecule of therapeutic value in treating inflammation.

Fig. 29. Lantern-like fruits of Physalis alkekengi.

CONCLUSION AND FUTURE PROSPECTS

In summary, most of the evidence that has emerged from the investigation of medicinal plants of Asia and the Pacific for anti-inflammatory principles shows a clear predominance of sesquiterpene lactones from Asteraceae, which are able to inhibit the enzymatic activity of lipo-oxygenase, COX, NOS, and elastase, and we can reasonably expect the isolation of original anti-inflammatory drugs from this large family. Some evidence has already been presented that indicates that a large number of flowering plants owe their anti-inflammatory properties to flavonoids which inhibit a broad spectrum of enzymes and scavenge free radicals.

Such plants might be found in the Asteridae, particularly in the order Lamiales (Boraginaceae, Verbenaceae), Solanales (Convolvulaceae), Scrophulariales (Acan-thaceae), Dipsacales (Caprifoliaceae), and Rubiales (Rubiaceae). Cordia verbenacea DC, Cordia francisci, Cordia myxa, and Cordia serratifolia in the Boraginaceae exhibit significant analgesic, anti-inflammatory, and antiarthritic properties in vivo (66). Another example of Boraginaceae is Carmona microphylla (Lamk.) Don, which is known to produce quinones, ehretianone, and microphyllone, and which has exhibited anti-inflammatory potencies in vivo and in vitro (67).

The family Convolvulaceae consists of 50 genera and 1500 species of vines is of substantial interest in the search for COX inhibitors because it is known that the phenolic compounds it elaborates, such as eugenol and N-trans- and N-cis-feruloyl-tyramines, inhibit the synthesis of PG. Note that the closely related Solanaceae are known to elaborate feruloyltyramines and could be also considered as a source of COX inhibitors. One of these, Argyreia speciosa, at the doses of 50, 100, and 200 mg/kg dose-dependently potentiates the delayed-type hypersensitivity reaction induced both by sheep red blood cells and oxazolone in rodents (68). Vitex negundo L. (Verbenaceae) abrogates carrageenan- and formaldehyde-induced paw edema, inhibits antihistamine and PG synthesis, and stabilizes membrane and fight oxidation (69,70). An ethanolic extract of the leaves of Graptophyllum pictum (L.) Griffith (Acanthaceae) given orally to rodents is anti-inflammatory (71). Acanthus ebracteatus reduces the production of eicosanoid (72) and abrogates the edema induced by carrageenan in rats. In the Rubiaceae, extracts of Paederia foetida L. inhibit significantly the formation of granulation in cotton-pellet-implanted rats (73). Note that anthocyanins and hydrolysable tannins (Rosidae, Hamamelidae) are anti-inflammatory because of their ability to scavenge free radicals, as in the case of aqueous extract of Bridelia ferruginea, which inhibits paw edema induced by carrageenan, with an ID50 value of 36 mg/kg (74). Triterpene as anti-inflammatory principles are to be found particularly in the subclass Dilleniidae and especially in the Ebenaceae (Diospyros species) and Capparaceae (Crateva species), and are known to elaborate a series of pentacyclic triterpenes including betulin, betulinic acid, and ursolic acid.

Crataeva Magna

Lupeol, isolated from the stem bark of Crataeva magna (Lour.) DC. (Capparaceae), reduces the foot-pad thickness and complement activity in arthritic rats (75). Oleano-lic acid saponins isolated from the roots of Momordica cochinchinensis (Lour.) Spreng. is anti-pruritic in rodent (76).

In comparison to the Asteraceae, Dilleniidae, and Rosidae, evidence available regarding the anti-inflammatory effects of Caryophyllaceae seems vestigial, hence the urgent need to assess this subclass for its anti-inflammatory potentials.

Caryophyllidae are an interesting source of oligosaccharides and peptides with potential anti-inflammatory and/or immunomodulating effect. These polar compounds might for instance explain the fact that the fresh juice expressed from Aerva lanata (L.) Juss. (Amaranthaceae) inhibits carrageenan-induced edema in rodent. Note that the seeds of Gomphrena species inhibit the formation of IL-6 by osteoblastic cells (MC3T3-E10) without cytotoxicity in vitro. Such property could be useful for the treatment of chronic rheumatoid arthritis, infection, and cancer. In the Lauraceae, trans-cinnamal-dehyde from Cinnamomum cassia (Lauraceae, order Laurales) inhibits in vitro the activity of NOS. African medicinal plants Cinnamomum latifolia Sonder, Cinnamomum myrtifolia Stapf., Cinnamomum transvaalensis Burtt. Davy, Cinnamomum woodii Engl., and Cinnamomum wyliei Stapf., exhibited in vitro potent inhibition of COX-2 (77).

Hong et al. (7) evaluated approx 170 methanol extracts of natural products, including Korean herbal medicines, for the inhibition of PGE2 production (for COX-2 inhibitors) and NO formation (for iNOS inhibitors) in LPS-induced mouse macrophage RAW 264.7 cells. As a result, several extracts, such as Aristolochia debilis (Aristolochi-aceae), Cinnamomum cassia and Cinnamomum loureiroi (Lauraceae), Curcuma zedoaria (Zingiberaceae), Eugenia caryophyllata (Myrtaceae), Pterocarpus santalius (Fabaceae), Rehmania glutinosa (Scrophulariaceae), and Tribulus terrestris (Zygophyllaceae), showed potent inhibition of COX-2 activity (>80% inhibition at the test concentration of 10 (ig/mL). In addition, the extracts of Aristolochiaceae debilis, Caesalpinia sappan, Curcuma longa, Curcuma zedoaria, Daphne genkwa (Thymeleaceae), and Morus alba (Moraceae) were also considered as potential inhibitors of iNOS activity (>70% inhibition at the test concentration of 10 mg/mL). Investigation of these active extracts mediating COX-2 and NOS inhibitory activities are warranted for further elucidation of active principles for development of new cancer chemopreventive and/or anti-inflammatory agents.

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