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*****ACTA GINECOLOGICA*****
Llombart A  Perez-Minguez F  
[METAPHASE BLOCK AND MITOTIC INHIBITION OF EHRLICH ASCITES CARCINOMA PRODUCED BY
A LACTOSE SESQUITERPENE ISOLATED FROM CENTAUREA ASPERA]
In: Acta Ginecol (Madr) (1969) 20(2):135-142
ISSN: 0001-5776  (Published in Spanish)

In mice with Ehrlich ascites carcinoma, admin of an optimal therapeutic dose (1
mg/20 g) of a lactose sesquiterpene from Centaurea aspera stenophylla caused max
inhibition of mitosis in the tumor cells at 12 hr after inj, followed by a
return of the mitotic rate to slightly above pretreatment values by 120 hr.
Other morphological changes observed in the tumor cells included metaphase
arrest (similar to that caused by colchicine), other chromosomal changes and
pyknosis.

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*****ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE*****
Ivorra MD  D'Ocon MP  Paya M  Villar A  
Antihyperglycemic and insulin-releasing effects of beta-sitosterol 3-
beta-D-glucoside and its aglycone, beta-sitosterol.
In: Arch Int Pharmacodyn Ther (1988 Nov-Dec) 296:224-31
ISSN: 0003-9780

The effect of beta-sitosterol 3-beta-glucoside (antihyperglycemic principle
isolated from the aerial part of Centaurea seridis L. var. maritima Lge.) and
its aglycone on plasma insulin and glucose levels in normo- and hyperglycemic
rats was investigated. The results indicate that oral treatment with the
glycoside or with the beta- sitosterol increased the fasting plasma insulin
levels. There was a corresponding decrease in fasting glycemia when
beta-sitosterol was administered orally. In addition, these compounds improved
the oral glucose tolerance test with an increase in glucose-induced insulin
secretion. But when these products were administered orally, the effect of
glycoside, either on fasting insulinemia or on glucose- induced insulin
secretion, lasted longer than that of aglycone. The present study compared these
effects with those of glibenclamide. It can be assumed that beta-sitosterol
3-beta-D-glucoside acts by increasing circulating insulin levels, and that this
effect is due to their aglycone: beta-sitosterol.

Registry Numbers:
11061-68-0 (Insulin)
474-58-8 (lyoniside)
50-99-7 (Glucose)
5779-62-4 (sitosterol)

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*****BRITISH JOURNAL OF PHARMACOLOGY*****
Hay AJ  Hamburger M  Hostettmann K  Hoult JR  
Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes
caused by their chemically reactive alpha- methylenebutyrolactone functions.
In: Br J Pharmacol (1994 May) 112(1):9-12
ISSN: 0007-1188

1. Previous studies have shown that extracts of feverfew (Tanacetum parthenium)
and parthenolide, a sesquiterpene alpha- methylenebutyrolactone obtained from
it, inhibit smooth muscle contractility in a time-dependent, non-specific and
irreversible manner. 2. The hypothesis that this toxic effect is due
specifically to the presence in the sesquiterpene lactone of the potentially
reactive alpha-methylene function was tested on rabbit isolated aortic ring
preparations. This was done (a) by comparing the effects of two plant-derived
sesquiterpene lactones purified from yellow star thistle (Centaurea
solstitialis): cynaropicrin (an alpha- methylenebutyrolactone) and solstitialin
13-acetate (lacking the alpha-methylene function), and (b) by chemically
inactivating the alpha-methylene functions in cynaropicrin and parthenolide by
reaction with cysteine. 3. The results show that the characteristic smooth
muscle inhibitory profile is demonstrated by the two alpha-
methylenebutyrolactones (parthenolide and cynaropicrin), but not by the compound
lacking this functional group (solstitialin 13-acetate), or by those previously
active compounds in which it has been inactivated with cysteine. 4. Thus the
alpha-methylene function is critical for this aspect of the toxic
pharmacological profile of the sesquiterpene butyrolactones, which are natural
products widely distributed in the Compositae family of flowering plants.

Registry Numbers:
22738-70-1 (solstitialin)
29552-41-8 (parthenolide)
35730-78-0 (cynaropicrin)
4371-52-2 (Cysteine)
59-42-7 (Phenylephrine)

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*****JOURNAL OF ETHNOPHARMACOLOGY*****
Lietava J  
Medicinal plants in a Middle Paleolithic grave Shanidar IV?
In: J Ethnopharmacol (1992 Jan) 35(3):263-6
ISSN: 0378-8741

This paper deals with phytopharmacological evaluation of the therapeutic
potential of the plants found in the Neanderthal grave of a Shanidar IV
individual (Iraq), where the palynological analysis of some other authors
discovered the following flowers: Achillea-type, Centaurea solstitialis,
Senecio-type, Muscari-type, Ephedra altissima, Althea-type. The purpose of our
theoretical analysis was to evaluate the objective healing activity of the
flowers. The result of the research revealed that Shanidar IV flowers possess
considerable therapeutic effects with marked medical activity, which could be an
intentional reason for the selection of the flowers in Middle Paleolithic
Shanidar Neanderthals.

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Twaij HA  Kery A  Al-Khazraji NK  
Some pharmacological, toxicological and phytochemical investigations on
Centaurea phyllocephala.
In: J Ethnopharmacol (1983 Dec) 9(2-3):299-314
ISSN: 0378-8741

Centaurea phyllocephala Boiss. has been used in folkloric medicine as an
antidiabetic agent. Present investigations on various extracts of C.
phyllocephala revealed that basal plasma glucose concentration and plasma
glucose response to glucose load were either elevated or unchanged by the i.v.
administration of these extracts in anaesthetized rats or by i.p. or oral
administration of the extracts in conscious rats. The predominant effect of C.
phyllocephala is the toxicity in rats and mice and this indicates the presence
of some toxic or active compounds which merit phytochemical isolation. Further,
C. phyllocephala extracts also caused either an initial brief hypotension
followed by a delayed hypertension or produced no changes when injected i.v. in
the rats. The hypotensive effect was inhibited by atropine whereas the
hypertensive effect was prevented by phentolamine or guanethidine but not by
hexamethonium. The alcoholic extract also induced an initial brief negative
inotropic effect, followed by delayed prolonged positive inotropic and negative
chronotropic effects on the spontaneous inotropic and negative chronotropic
effects on the spontaneous contractions of the guinea pig right atrium. The
initial depressing effect and the delayed positive inotropic effect were
inhibited by pretreatment with atropine. The extract of C. phyllocephala also
produced a contractile activity on guinea pig ileum strips and this could be
prevented by atropine. No significant diuretic effect was produced by the
extract. Phytochemical screening revealed that C. phyllocephala contains
tertiary and quaternary alkaloids, sesquiterpene lactones, methylated flavones
and their glycosides, as well as leuco- and proanthocyanidines. Further studies
on sesquiterpene lactones and methylated flavones resulted in the isolation of
lactones with alpha- methylene gamma-lactone and methylene side chain on the
cyclopentyl ring as well as of four methylated flavones (hispidulin, nepetin,
cirsiliol, jaceosidin) structurally closely related to the cytotoxic flavonoids
of other Compositae plants.

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Negrete RE  Backhouse N  Cajigal I  Delporte C  Cassels BK   Breitmaier E 
Eckhardt G  
Two new antiinflammatory elemanolides from Centaurea chilensis.
In: J Ethnopharmacol (1993 Dec) 40(3):149-53
ISSN: 0378-8741

Two previously undescribed elemanolide esters, the 2-methylpropanoate and
2-methyl-2-propenoate of 11,13-dehydromelitensin, were isolated in the course of
a bioassay-guided fractionation from the aerial parts of Centaurea chilensis
Hook. et Arn., used traditionally to treat 'gout and rheumatism'. The mixture of
both substances exhibits anti-inflammatory activity in the carrageenan-induced
paw edema assay.

Registry Numbers:
9000-07-1 (Carrageenan)

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*****JOURNAL OF NATURAL PRODUCTS*****
Lonergan G  Routsi E  Georgiadis T  Agelis G  Hondrelis J  Matsoukas J   Larsen
LK  Caplan FR  
Isolation, NMR studies, and biological activities of onopordopicrin from
Centaurea sonchifolia.
In: J Nat Prod (1992 Feb) 55(2):225-8
ISSN: 0163-3864

A sesquiterpene lactone, onopordopicrin [1], has been isolated from Centaurea
sonchifolia. Its structure was established by 2D nmr (1H-1H and 13C-1H
correlations), and the conformation in CHCl3 was examined by nOe studies.
Cytotoxic, antibacterial, and antifungal activities are reported.

Registry Numbers:
19889-00-0 (onopordopicrin)

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Navarro JJ  Caballero MC  Moran JR  Medarde M  Grande M  Anaya J  
Guaianolides and eudesmanolides from Centaurea ornata.
In: J Nat Prod (1990 May-Jun) 53(3):573-8
ISSN: 0163-3864

Four sesquiterpene lactones and three other compounds have been isolated from
the EtOH-H2O-soluble fraction of a CHCl3 extract of Centaurea ornata. A new
grosshemin derivative 3 is described, and the stereochemistry of natural
11-epi-dihydroreynosin [2] is revised.

Registry Numbers:
121-33-5 (vanillin)
19103-54-9 (salvigenin)
32223-12-4 (dihydroreynosin)
36651-81-7 (5-methyl-8-hydroxycoumarin)
4290-13-5 (santamarine)

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*****JOURNAL OF NEUROSCIENCE RESEARCH*****
Robles M  Wang N  Kim R  Choi BH  
Cytotoxic effects of repin, a principal sesquiterpene lactone of Russian
knapweed.
In: J Neurosci Res (1997 Jan 1) 47(1):90-7
ISSN: 0360-4012

Repin is the principal sesquiterpene lactone isolated from Russian knapweed
(Centaurea repens), a perennial weed found in many parts of the United States.
Ingestion of Centaurea repens by horses has been reported to cause a movement
disorder simulating Parkinson's disease (PD) and nigrostriatal degeneration,
called equine nigrostriatal encephalomalacia (ENE). To understand the mechanisms
whereby ingestion of Centaurea repens induces ENE and a PD-like disorder, repin
cytotoxicity was examined to explore its pathogenetic relationship to ENE and to
PD. Repin was highly cytotoxic to both PC12 cells and mouse astrocytes in a
dose- and time-dependent manner. The cytotoxic effects were accompanied by
depletion of glutathione (GSH), a rise in the level of reactive oxygen species
(ROS) and damage to cellular membranes. Although repin is a highly reactive
electrophile that can readily conjugate GSH, GSH depletion may not be the sole
mechanism underlying repin cytotoxicity as shown by our study using buthionine
sulfoximine, in which severe GSH depletion did not result in a parallel increase
in cell death. However, pre- treatment with GSH-glycoside or with lipoic acid
provided significant protection from repin-induced cell death. These data
suggest that oxidative stress plays a major role in repin cytotoxicity. Since
oxidative stress is considered to play a major role in neuronal degeneration
accompanied by depletion of mitochondrial GSH and an increase in lipid peroxides
in the substantia nigra of PD, further elucidation of mechanisms of repin
neurotoxicity may generate clues regarding not only the mechanisms of neuronal
degeneration but also the possible role of environmental factors in the
pathogenesis of PD.

Registry Numbers:
11024-67-2 (repin)
5072-26-4 (Buthionine Sulfoximine)
62-46-4 (Thioctic Acid)
70-18-8 (Glutathione)

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*****NATURAL TOXINS*****
Roy DN  Peyton DH  Spencer PS  
Isolation and identification of two potent neurotoxins, aspartic acid and
glutamic acid, from yellow star thistle (Centaurea solstitialis).
In: Nat Toxins (1995) 3(3):174-80
ISSN: 1056-9014

Horses grazing for prolonged periods on yellow star thistle (YST), a plant which
grows wild in western parts of the United States, develop an extrapyramidal
disorder known as nigropallidal encephalomalacia (NPE). Attempts have been made
to identify, isolate, and characterize the toxins responsible for the disease in
animals. Using the organotypic tissue culture system on mouse cortical explants
as a specific assay method for neurotoxicological evaluation, it has been
possible to isolate and characterize two potent neuroexcitotoxic compounds,
aspartic and glutamic acids, the former being the major toxic component in the
alcoholic extract of the plant. There is also evidence that other neurotoxic
compounds are present in the extract. The detailed procedure for isolation and
characterization of these compounds is given here.

Registry Numbers:
56-84-8 (Aspartic Acid)
56-86-0 (Glutamic Acid)

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Hamburger M  Wolfender JL  Hostettmann K  
Search for chlorinated sesquiterpene lactones in the neurotoxic thistle
Centaurea solstitialis by liquid chromatography-mass spectrometry, and model
studies on their possible artifactual formation.
In: Nat Toxins (1993) 1(6):315-27
ISSN: 1056-9014

An HPLC method has been developed for the analysis of sesquiterpene lactones of
the neurotoxic plant Centaurea solstitialis (Asteraceae). The presence of
sesquiterpene lactone chlorohydrins in extracts was investigated by means of
liquid chromatography-thermospray mass spectrometry. In contrast to earlier
reports of a series of mono- and dichlorohydrins from this plant, traces only of
two monochlorohydrins could be detected in lipophilic extracts. Model studies
carried out with extracts and with the genuine sesquiterpene diepoxide repin and
its epimer subluteolide showed that (i) monochlorohydrins can be formed in CHCl3
under usual laboratory conditions; (ii) the epoxide moiety at C-4 of the
sesquiterpenes is extremely labile, reacting immediately and quantitatively with
traces of HCl to the corresponding monohydrins; (iii) epoxide ring opening at
the acyl side chain occurs only at higher HCl concentrations. Confirmation of
the peak identity was obtained by the isotope ratio of chlorinated compounds and
comparison with authentic samples. The structures of the mono- and
dichlorohydrins were established by NMR spectroscopy.

Registry Numbers:
7782-50-5 (Chlorine)

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*****PHARMAZIE*****
Ivorra MD  Paya M  Villar A  
Effect of beta-sitosterol-3-beta-D-glucoside on insulin secretion in vivo in
diabetic rats and in vitro in isolated rat islets of Langerhans.
In: Pharmazie (1990 Apr) 45(4):271-3
ISSN: 0031-7144

Beta-Sitosterol-3-beta-D-glucoside (1) has been reported to be the active
antidiabetic agent of Centaurea seridis L. var. maritima. The present study
examines the effect of oral administration of this compound on plasma insulin
and glucose levels in streptozotocin- induced diabetic rats and its influence on
insulin release from isolated rat islets. The results indicate that 1 did not
change insulin and glucose levels in rats with severe diabetes. 1 stimulated
insulin release from isolated rat islets in the presence of a non- stimulatory
glucose concentration but did not increase the insulin releasing capacity of
glucose (16 mmol/l). These data suggest that 1 exerts its action on intact
pancreatic beta-cells by stimulating insulin secretion.

Registry Numbers:
11061-68-0 (Insulin)
474-58-8 (lyoniside)

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*****PLANTA MEDICA*****
Bruno M  Fazio C  Paternostro MP  Diaz JG  Herz W  
Sesquiterpene lactones and other constituents of Centaurea napifolia [letter]
In: Planta Med (1995 Aug) 61(4):374-5
ISSN: 0032-0943

Aerial parts of Centaurea napifolia furnished the sesquiterpene lactones cnicin,
4'-acetoxycnicin, melitensin, dehydromelitensin, two known esters of
dehydromelitensin, lappaol and a lappaol isomer, and a 1,2-diacylated glucose.

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*****REVISTA ESPANOLA DE FISIOLOGIA*****
Masso JL  Adzet T  
[Hypoglycaemic activity of centaurea aspera L (author's transl)]
Actividad hipoglucemiante de Centaurea aspera L
In: Rev Esp Fisiol (1976 Dec) 32(4):313-6
ISSN: 0034-9402  (Published in Spanish)

Two aquous crude extracts of Centaurea aspera L. flowers were tested for
hypoglycaemic activity in normal and alloxan-diabetic rats. Both extracts exert
a significant hypoglycaemic effect by oral route and chronic administration in
diabetic rats, but only the extract obtained by exhaustion with hot water
displayed an acute hypoglycaemic activity in normal animals. All plant-treated
groups were compared against glibenclamide as a standard. The acute toxicity by
oral and intravenous routes was determined in mice.

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