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Acute anti-inflammatory activity of four saponins isolated from ivy: Alpha-hederin, hederasaponin-C, hederacolchiside-E and hederacolchiside-F in carrageenan-induced rat paw edema


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The anti-inflammatory potential of alpha-hederin (monodesmoside) and hederasaponin-C from Hedera helix, and hederacolchisides-E and -F (bidesmosides) from H. colchica was investigated in carrageenan-induced acute paw edema in rats. Saponins and indomethacin were given orally in concentrations of 0.02 and 20mg/kg body wt. For the first phase of acute inflammation, indomethacin was found as the most potent drug. Alpha-hederin and hederasaponin-C were found ineffective, while hederacolchisides-E and -F showed slight anti-inflammatory effects on the first phase. For the second phase of acute inflammation, indomethacin and hederacolchiside-F were determined as very potent compounds. alpha-hederin was found ineffective for the second phase, either. Despite hederasaponin-C and -E were found effective in the second phase of inflammation, they were not found as effective as indomethacin and hederacolchiside-F. As a conclusion, hederasaponin-C, -E and -F, may exert their anti-inflammatory effects by blocking bradykinin or other inflammation mediators. The latter affect may occur via affecting prostaglandin pathways. Regarding the structure activity relationship, it is likely that sugars at C3 position and Rha7-Glcl-6Glc moiety at C28 position are essential for the acute anti-inflammatory effect.
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Phytomedicine 12 (2005) 440–444
Acute anti-inflammatory activity of four saponins isolated from ivy:
alpha-hederin, hederasaponin-C, hederacolchiside-E and
hederacolchiside-F in carrageenan-induced rat paw edema
A. Gepdiremen
, V. Mshvildadze
, R. Elias
Department of Pharmacology, Medical Faculty, Ondokuz Mayis University, TR-55050 Kurupelit, Samsun-Turkey
Institute of Pharmacochemistry, 36, St.P.Sarajishvili, 380059 Tbilisi, Georgia
Laboratory of Pharmacognosy and Homeopathy, Pharmacy Faculty of Mediterranean, University of Marseille, 27 Bd.,
J.Moulin, 13385 Marseille, France
Received 28 October 2003; accepted 1 April 2004
The anti-inflammatory potential of a-hederin (monodesmoside) and hederasaponin-C from Hedera helix,and
hederacolchisides-E and -F (bidesmosides) from H. colchica was investigated in carrageenan-induced acute paw edema
in rats. Saponins and indomethacin were given orally in concentrations of 0.02 and 20 mg/kg body wt. For the first
phase of acute inflammation, indomethacin was found as the most potent drug. a-hederin and hederasaponin-C were
found ineffective, while hederacolchisides-E and -F showed slight anti-inflammatory effects on the first phase. For the
second phase of acute inflammation, indomethacin and hederacolchiside-F were determined as very potent
compounds. a-hederin was found ineffective for the second phase, either. Despite hederasaponin-C and -E were
found effective in the second phase of inflammation, they were not found as effective as indomethacin and
hederacolchiside-F. As a conclusion, hederasaponin-C, -E and -F, may exert their anti-inflammatory effects by
blocking bradykinin or other inflammation mediators. The latter affect may occur via affecting prostaglandin
pathways. Regarding the structure activity relationship, it is likely that sugars at C
position and Rha7-Glc1-6Glc
moiety at C
position are essential for the acute anti-inflammatory effect.
r2005 Elsevier GmbH. All rights reserved.
Keywords: Saponins of ivy, Hedera helix; Anti-inflammatory activity; Carrageenan; a-hederin; Hederasaponin; Hederacolchiside
Hedera helix (Hedera helix L.) is a well-known plant
as ivy or English ivy, and is a member of Araliaceae
family. Especially the fresh form of leaves and fruits are
toxic, cause gastrointestinal irritation, bloody diarrhea
and death (Baytop, 1984). The best known effect of this
plant is to cause contact dermatitis (Garcia et al., 1995).
Additionally, antibacterial (Cioaca et al., 1978), anti-
helmintic (Julien et al., 1985), leishmanicidic (Majester-
Savornin et al., 1991), in vitro antispasmodic (Trute et
al., 1997), antifungal (Moulin-Traffort et al., 1998)and
acute and chronic anti-inflammatory (Su
¨leyman et al.,
2003) effects of H. helix extracts were reported. On the
0944-7113/$ - see front matter r2005 Elsevier GmbH. All rights reserved.
Corresponding author. Tel.: +90 5354883305;
fax: +90 3624576041.
E-mail address: (A. Gepdiremen).
other hand, H. colchica K. Koch is a less known member
and only antifungal and antiprotozoal activities were
investigated by now (Mshvildadze et al., 2000). Also,
hederacolchiside A1 was tested against proliferation of
human carcinoma and melanoma, recently (Barthomeuf
et al., 2002). It has been demonstrated that bidesmosides
were more active in in vivo experiments than mono-
desmosides (Julien et al., 1985).
It is well known that to investigate the effects of
drugs on the acute phase of inflammation, models
induced by pro-inflammatory agents such as carragee-
nan, dextrane, formaldehyde, serotonin, histamine
and bradykinin in rat paws are employed (Campos
et al., 1995). Carrageenan is perhaps the most com-
monly used and well studied of these phlogistics
(Leme et al., 1973) producing a maximal edema in 3 h.
While the carrageenan model is typically associated
with activation of the cyclo-oxygenase pathway and is
sensitive to glucocorticoids and prostaglandin synthesis
antagonists, the early phase of the carrageenan response
is due to the release of serotonin and histamine (DiRosa
et al., 1971).
In this study, we tested the possible anti-inflammatory
effects of the saponins named a-hederin (AH) and
hederasaponin-C (HsC) extracted from H. helix, and
hederacolchiside-E (HcE) and hederacolchiside-F (HcF)
extracted from H. colchica, in carrageenan-induced
acute paw edema in rats (see Fig. 1).
Material and methods
Plant material
The leaves of H. colchica were collected in the Bagdati
region of West Georgia, in September 2000, and the
leaves of H. helix were collected in Marseille-France, in
September 1999. The materials were identified by Riad
Elias, a staff member of the Laboratory of Pharmacog-
nosy and Homeopathy, Pharmacy Faculty of Mediter-
ranean University, Marseille, France. Vaucher specimen
of the leaves of H. colchica is kept in the Department of
Pharmacobotany, Institute of Pharmacochemistry, Tbi-
lisi, Georgia (leaves no: 70996). Vaucher specimen of the
leaves of H. helix is kept in the Laboratory of
Pharmacognosy, Mediterranean University, Marseille,
France (leaves no: 135797).
Isolation and characterization of hederasaponin C
and a-hederin have been described in previous reports
(Elias et al., 1991). The BuOH extract (2.5 g) of the
leaves of H. helix L., was subjected to low-pressure
chromatography (LPC) on Rp 18, with gradient of
MeOH in H
O to yield pure hederasaponin C (1 g).
Alpha-hederin was obtained by alkaline hydrolysis of
hederasaponin C. Hederacolchisides E and F were
isolated from the methanolic extract of leaves of H.
colchica K. Koch, as it was described by other authors
(Dekanosidze et al., 1984). The structures of isolated
30 29
25 CO2R3
Fig. 1. The chemical structures of triterpene glycosides isolated from H. colchica K. Koch and H. helix L. (Araliaceae).
Name R
Hederacolchiside E (HCE) Rha 1-2 [Glcl-4]Ara H Rha 1-4 Glcl-6Glc
Hederacolchiside F (HCF) Rha 1-2 [Glcl-4]Ara OH Rha 1-4 Glcl-6Glc
Hederasaponin C (HSC) Rha 1-2 Ara OH Rha 1-4 Glcl-6Glc
Alpha-Hederin (A-H) Rha 1-2 Ara OH H
Ara: a-L-arabinopyranosyl, Rha: a-L-rhamnopyranosyl and Glc: b-D-glucopyranosyl
A. Gepdiremen et al. / Phytomedicine 12 (2005) 440–444 441
compounds were established on the base of MS and
H and
C NMR methods and the data are in
good agreement with literature values. Optical rotation
for: AH: +9.681(EtOH), HsC: +78.8 (MeOH), HcE:
22.28 (MeOH), HcF: 0 (MeOH). Purity of isolated
compounds were determined by HPLC method: AH
and HsC have 99% purity, while HcE and HcF have
98% of purity. For detailed chemical structure, please
refer to Fig. 1.
In this study, 42 adult male Wistar albino rats
weighing 180–210 g, and obtained from Atatu
¨rk Uni-
versity, Faculty of Medicine, Department of Pharma-
cology, Experimental Animal Laboratory, were used.
The rats were fed with standard laboratory chow and
tap water before the experiment. The animal laboratory
was equipped with automatic temperature (22711C)
and lighting controls (14 h light/10 h dark). The rats
were divided into groups, each containing 7 individuals.
The investigation conforms with the Guide for the Care
and Use of Laboratory Animals published by the US
National Institutes of Health (NIH Publication No. 85-
23, revised 1996) and the procedures were approved by
the University ethics committee.
Anti-inflammatory studies
Anti-inflammatory effects of AH, HsC, HcE and HcF
were investigated in an aseptic arthritis model, in
0.02 mg/kg (dissolved in 1 ml of water), while indo-
methacin, in 20 mg/kg (dissolved in 1 ml of water) doses
were given to the rats orally by feeding tube as positive
controls. For control animals, 1 ml of water was
administered in the same protocol. The ratio of the
anti-inflammatory effect of the extracts were calculated
by the following equation: Anti-inflammatory activity
(%) ¼(1D/C)100, where Drepresents the percentage
difference in paw volume after the compounds were
administered to the rats, and Crepresents the percen-
tage difference of the volume in the control group.
Carrageenan-induced paw edema
The compounds were given once daily for 2 days. Two
hours after the final administration of the compounds,
0.1 ml (1%, w/v) carrageenan solution in distilled water
was subcutaneously injected into the plantar surface of
the right hind paw. The paw volume was measured with
a plethysmometer three times; once before injection, and
then, 1 and 4 h following the carrageenan administra-
tion. The anti-inflammatory activities in animals that
received AH, HsC, HcE and HcF were compared
with that of indomethacin and the control groups (see
Table 1).
Statistical analysis
Values are presented as mean7SEM. Independent
samples-ttest and analysis of variance (ANOVA,
Dunnett method) were used for the evaluation of data
and po0:05 was accepted as statistically significant.
HsC, HcE and HcF were found to have anti-
inflammatory effects in carrageenan-induced acute
phase of inflammation. In ANOVA test, F-ratio was
2.36 and F-probability was found as 0.053, for first hour
measurements, while F-ratio was 3.57 and F-probability
was 0.0074, for fourth hour measurements. The most
effective drug was found to be indomethacin
(22.0374.1%, po0:001 in respect to control group)
for first hour measurements. HcE (32.3374.9%,
po0:05 in respect to control group) and HcF
(32.175.4%, po0:05 in respect to control group) were
found slightly effective, and AH and HsC were found
statistically ineffective, in that period. Values represent
Table 1. Effects of saponins on carrageenan-induced rat paw edema
Treatment Dose (mg/kg) nEdema rate percentage (mean7SEM)
1h p4h p
Control 7 49.274.5 — 57.475.7 —
Indomethacin 20 7 22.0374.1 o0.001 29.3272.6 o0.001
Alpha hederin 0.02 7 39.674.3 40.05 42.876.7 40.05
Hederasaponin-C 0.02 7 39.275.6 40.05 36.2974.7 o0.01
Hederacolchiside-E 0.02 7 32.3374.9 o0.05 36.9175.1 o0.05
Hederacolchiside-F 0.02 7 32.175.4 o0.05 29.175.2 o0.001
Groups compared to controls, by independent samples-ttest.
A. Gepdiremen et al. / Phytomedicine 12 (2005) 440–444442
percent increase in respect to first measurements of each
For fourth hour measurements, except AH, all the
groups tested has been found effective. Despite the AH
administered group results (42.876.7%) were found
better than the control (57.475.7%), it was statistically
insignificant. Hederacolchiside-F (29.175.2%, po0:001
in respect to control group) was found as effective as
indomethacin (29.3272.6%, po0:001 in respect to
control group), while HsC (36.2974.7%, po0:01 in
respect to control group) and HcE (36.9175.1%,
po0:05 in respect to control group) exerted lesser anti-
inflammatory effects within the fourth hour of inflam-
mation. Values represent percent increase in respect to
first measurements of each group (Table 1).
Several triterpene saponins have been tested in several
applications by now. Buddlejasaponin and saikosapo-
nin’s in vivo anti-inflammatory effect on mouse ear
edema (Bermejo-Benito et al., 1998) and zanhasaponin’s
acute and chronic anti-inflammatory effects (Cuellar et
al., 1997) were shown before. It was reported that the
anti-inflammatory effects of several agents result in the
partial inhibition of inflammation mediator release
(Amadio et al., 1993). Subcutaneous injection of
carrageenan into the rat paw produces plasma extra-
vasation (Szolcsanyi et al., 1998) and inflammation,
characterized by increased tissue water and plasma
protein exudation with neutrophil extravasation and
metabolism of arachidonic acid by both cyclooxygenase
and lipoxygenase enzyme pathways (Gamache et al.,
In the present study, all the saponin groups and
indomethacin, except AH, exerted anti-inflammatory
effects, in respect to control. Despite HcF and indo-
methacin found as effective as each other, regarding the
doses of 20 mg/kg for indomethacin and 0.02mg/kg for
HcF, it may be speculated that HcF is a more potent
compound than indomethacin for the second phase of
inflammation. Contrary the results of AH and HsC
application, HcE and HcF, in very low doses, were
found quite effective to prevent acute phase of
inflammation for the same period. For the first phase
of acute inflammation, we found indomethacin as the
most potent compound, tested in the present study.
There are biphasic effects in carrageenan-induced
edema. The first phase begins immediatelly after
injection and diminishes within 1 h. The second phase
begins at 1 h and remains through 3 h (Garcia-Pastor et
al., 1999). It is suggested that the early hyperemia of
carrageenan-induced edema results from the release of
histamine and serotonin (Kulkarni et al., 1986). The
delayed phase of carrageenan-induced edema results
mainly from the potentiating effects of prostaglandins
on mediator release, especially of bradykinin. Hydro-
cortisone and some NSAIDs strongly inhibit the second
phase of carrageenan-induced edema, but some others
are effective against both phases (Kulkarni et al., 1986).
According to that, indomethacin seems to block both
phases, that means blocking histamin and serotonin
release within the first hour, and it also prevents
releasing some of the inflammatory mediators, via
blocking the prostaglandin’s action within the second
phase. On the other hand, saponin derivatives (except
AH), seem to affect mainly the second phase of acute
inflammation. Despite the fact that both, hederacolchi-
side-E and -C, found slightly effective on that period,
this effect was not as obvious as indomethacin or
hederacolchiside-F. So, it is very likely that, HsC and
HcE exert their anti-inflammatory effects by blocking
bradykinin or other inflammation mediators. The latter
effect of saponins may occur via affecting prostaglandin
pathways. HcF may affect some additional pathways,
similar to indomethacin.
Regarding their chemical structures (Fig. 1), HcE and
HcF with an additional glucose molecule in the sugar
chain at R1 position, are more active than AH and HsC.
So it may be speculated that, the glucose moiety in the
sugar residue connected to the C
position of the genin is
crucial for acute anti-inflammatory effect, especially for
the late phase of it. AH, monodesmoside with free
carboxyl group at C-17 position of the aglycone was
determined as a unique ineffective compound in the
present study. It could be supposed that, Rha1-4Glc1-
6Glc residue at R3 position may be responsible of the
anti-inflammatory effect.
The present study shows that HsC and HcE are slight
and HcF is a potent inhibitor of acute inflammation,
especially on the second phase. The mechanism of the
effect may depend on the inhibition of the formation of
some inflammatory mediators. In conclusion, detailed
studies are needed to clarify the mechanism(s) of anti-
inflammatory effects of saponins.
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A. Gepdiremen et al. / Phytomedicine 12 (2005) 440–444444
... The amount of this molecule can vary according to the type of species, the part used, the harvest season, as well as the geographical and climatic conditions. The identification and the chemical characterization of this natural molecule were carried out using several technologies, especially UPLC-ESI-MS and HPLC analysis, LC-EI/MS-MS, and MS, 1 H-and 13 C NMR methods [12][13][14][15]. ...
... α-Hederin ( Fig. 1) is the major compound in leaf extracts of Hedera helix L., commonly known as ivy in many countries (Table 1) [10,13,14,18,[30][31][32][33][34][35][36][37][38][39] and the stem extract of the same species collected in Austria and France [40][41][42]. The richness of plants in this compound depends on several geographic factors as well as on the plant part used . ...
... To extract, identify and isolate α-hederin different techniques has been sued. Indeed, UPLC-ESI-MS analysis, LC-EI/MS-MS, and MS, 1 H and 13 C NMR methods were used for the structural elucidation and purification of this molecule from the leaves of Hedera helix L. (Table 2) [12][13][14][30][31][32][33][34][35]37,39,56]. In addition, it was purified from the same plant (stems and whole plant) using HPLC-MS analysis [36, Extraction, identification, and isolation process of α-hederin. ...
α-Hederin is a natural bioactive molecule very abundant in aromatic and medicinal plants (AMP). It was identified, characterized, and isolated using different extraction and characterization technologies, such as HPLC, LC-MS and NMR. Biological tests have revealed that this natural molecule possesses different biological properties, particularly anticancer activity. Indeed, this activity has been investigated against several cancers (e.g., esophageal, hepatic, breast, colon, colorectal, lung, ovarian, and gastric). The underlying mechanisms are varied and include induction of apoptosis and cell cycle arrest, reduction of ATP generation, as well as inhibition of autophagy, cell proliferation, invasion, and metastasis. In fact, these anticancer mechanisms are considered the most targeted for new chemotherapeutic agents' development. In the light of all these data, α-hederin could be a very interesting candidate as an anticancer drug for chemotherapy, as well as it could be used in combination with other molecules already validated or possibly investigated as an agent sensitizing tumor cells to chemotherapeutic treatments.
... As it stands, these trimmings have shown to possess significant quantities of extractable pharmaceutically active compounds. 16 Extracts of CI are commercially applied as cough syrup (e.g., Prospan) and possess antioxidant, 17 antiinflammatory, 18 anticarcinogenic, 19 and antifungal properties. 20 A subsequent phase in the proposed biorefinery process uses the spent (extracted) CI residue stream as a feedstock for bioproduct manufacturing. ...
... Common Ivy Extracts as an Anti-inflammatory Agent. Gepdiremen et al. 18 studied the anti-inflammatory effects of both α-hederin and hederacoside C and two bidesmosides (hederacolchisides E and F) derived from H. colchica or Persian Ivy. They concluded that hederacoside C had a significant antiinflammatory effect; however, it was not as effective as hederacolchiside F or indomethacin (added as a positive control). ...
... Further, it was discovered that the bitter gourd's flesh has a significantly higher phenolic acid concentration than the inner tissues and seeds [27]. Phenolic compounds have antioxidant, insecticidal, antiparasitic, anti-inflammatory, antibacterial, anti-diabetic, wound healing, antidiuretic, cytotoxic, and antitumor activities [31,32]. Further studies on the isolation of unknown active principles from bitter gourd may bring out a new source for anti-inflammatory and anti-cancer drugs. ...
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Bitter gourd (Momordica charantia L.) contains rich bioactive ingredients and secondary metabolites; hence, it has been used as medicine and food product. This study systematically quantified the nutrient contents, the total content of phenolic acids (TPC), flavonoids (TFC), and triterpenoids (TTC) in seven different cultivars of bitter gourd. This study also estimated the organic acid content and antioxidative capacity of different cultivars of bitter gourd. Although the TPC, TFC, TTC, organic acid content, and antioxidative activity differed significantly among different cultivars of bitter gourd, significant correlations were also observed in the obtained data. In the metabolomics analysis, 370 secondary metabolites were identified in seven cultivars of bitter gourd; flavonoids and phenolic acids were significantly more. Differentially accumulated metabolites identified in this study were mainly associated with secondary metabolic pathways, including pathways of flavonoid, flavonol, isoflavonoid, flavone, folate, and phenylpropanoid biosyntheses. A number of metabolites (n = 27) were significantly correlated (positive or negative) with antioxidative capacity (r ≥ 0.7 and p < 0.05). The outcomes suggest that bitter gourd contains a plethora of bioactive compounds; hence, bitter gourd may potentially be applied in developing novel molecules of medicinal importance.
... The same was found for hederasaponin-C, while hederacolchisides-E and -F showed slight anti-inflammatory effects after one hour (p < 0.05). After four hours, hederacolchiside-F was found as effective as the control drug indomethacin (20 mg/kg), while hederacolchisides-C and -E were both effective, though less effective compared to indomethacin [99]. ...
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Reducing inappropriate antibiotic (AB) use by using effective non-antibiotic treatments is one strategy to prevent and reduce antimicrobial resistance (AMR). Andrographis paniculata (Burm. f.) Wall. ex Nees, Pelargonium sidoides DC., Echinacea species and a combination of ivy (Hedera helix L.), primrose (Primula veris L./Primula elatior L.) and thyme (Thymus vulgaris L./Thymus zygis L.) have promising clinical effects in uncomplicated, acute upper respiratory tract infections (URTI) treatment. However, mechanistic evidence of these herbal treatments is lacking. The objective of this Pstudy is to provide an overview of mechanistic evidence for these effects. Thirty-eight databases were searched. Included studies were mechanistic studies (in vitro, animal, and human studies and reviews) on these herbs; published before June 2021. Non-mechanistic studies or studies on combinations of herbs other than ivy/primrose/thyme were excluded. Furthermore, three experts in traditional, complementary and integrative healthcare (TCIH) research and pharmacognosy were interviewed to collect additional expert knowledge. The results show that A. paniculata acts through immunomodulation and antiviral activity, possibly supplemented by antibacterial and antipyretic effects. P. sidoides acts through antiviral, indirect antibacterial, immunomodulatory and expectorant effects. Echinacea species likely act through immunomodulation. The combination of ivy/primrose/thyme combines secretolytic and spasmolytic effects from ivy with antibacterial effects from thyme. Studies on primrose were lacking. This mechanistic evidence supports the difference-making evidence from clinical studies, contributes to evidence-based recommendations for their use in URTI treatment, and guides future mechanistic studies on URTI treatments.
... Противовоспалительную активность листьев плюща связывают с комбинированным действием флавоноидов и сапонинов [23]. Последние считаются наиболее эффективными на второй фазе воспаления [24], а флавоноиды могут проявлять ингибирующую активность в отношении фосфолипазы А2, циклооксигеназы-2 и ядерной транслокации нуклеарного фактора-κB (NFκB). К примеру, рутин тормозит NFκB-зависимую транскрипцию гена iNOS и, как следствие, синтез оксида азота, а хлорогеновая кислота снижает индуцированную липополисахаридами NFκB-зависимую циклооксигеназу-2 [25]. ...
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Although acute cough in acute inflammatory diseases of the upper respiratory tract seems to be a minor problem and can be stopped on its own, it holds the leading position among all reasons for population receiving health care due to significant decrease in life quality. Purpose. To analyze the cough severity in patients with acute nasopharyngitis with intoxication syndrome in the treatment of systemic non-steroidal anti-inflammatory drugs (NSAIDs) and local interferon therapy. Materials and methods. The study included 62 patients with acute nasopharyngitis with intoxication syndrome, in the period from the onset of the first symptoms to the visit to the doctor was no more than 24 hours. They were divided into 2 groups: group 1 − 32 people (14 men, 18 women, age 34.4±10.3 years) received traditional systemic therapy with NSAIDs, group 2 − 30 people (13 men, 17 women, age 41.1±13.7 years) received interferon-α2b intranasally. Cough severity was assessed using a 3-point visual analog scale (VAS) on the day of admission and for the next 7 days. Results. On the 1st day dry cough was observed in 62.5-63.3% of cases. Starting from the 3rd day of observation, there were statistically significant differences in the intensity of this symptom between the groups. In the traditional therapy of NSAIDs, an increase in the number of patients with a complaint of cough, and an increase in its severity compared with the first day of observation was revealed. They lasted until the 6th day of illness, which was explained by the spread of the inflammatory process to the trachea and bronchi. In the treatment of local interferon therapy, cough regression was noted on day 4 in 83.3% of cases, with its complete disappearance in this group on day 6. The total duration of cough in group 1 was 6.0 [5.0; 8.0] days, in group 2 - 2.0 [1.0; 3.0] days. Conclusion In acute inflammatory diseases of the upper respiratory tract, cough in the absence of prescribing drugs that affect this symptom persists on the eighth day of observation in 56.2% of patients with traditional therapy with systemic NSAIDs.
... According to proteomic sequencing analysis, AURKA, a classical cell cycle regulatory protein kinase, is highly expressed in NSCLC, and OP-B promotes ferroptosis in lung cancer in vitro and vivo by targeting AURKA [235]. α-heguelin is a monodesmotic triterpenoid saponin isolated from Hedera nepalensis K.Koch [236], which induces apoptosis at high doses, disrupts the redox system by significantly affecting glutathione metabolism at safe and low toxic doses to induce ferroptosis in NSCLC, and also increases the sensitivity of NSCLC cells to cisplatin [237]. ...
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Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer.
Acute kidney injury (AKI) is a common clinical condition associated with increased incidence and mortality rates. Hederasaponin C (HSC) is one of the main active components of Pulsatilla chinensis (Bunge) Regel. HSC possesses various pharmacological activities, including anti‐inflammatory activity. However, the protective effect of HSC against lipopolysaccharide (LPS)‐induced AKI in mice remains unclear. Therefore, we investigated the protective effect of HSC against LPS‐induced renal inflammation and the underlying molecular mechanisms. Herein, using MTT and LDH assays to assess both cell viability and LDH activity; using dual staining techniques to identify different cell death patterns; conducting immunoblotting, QRT‐PCR, and immunofluorescence analyses to evaluate levels of protein and mRNA expression; employing immunoblotting, molecular docking, SPR experiments, and CETSA to investigate the interaction between HSC and TLR4; and studying the anti‐inflammatory effects of HSC in the LPS‐induced AKI. The results indicate that HSC inhibits the expression of TLR4 and the activation of NF‐κB and PIP2 signaling pathways, while simultaneously suppressing the activation of the NLRP3 inflammasome. In animal models, HSC ameliorated LPS‐induced AKI and diminished inflammatory response and the level of renal injury markers. These findings suggest that HSC has potential as a therapeutic agent to mitigate sepsis‐related AKI.
The leaves of Colchis ivy (family Araliaceae) have yielded polar glycosides — hederacolchisides E and F — and their structures have been established. It has been shown on the basis of the results of methylation and of acid and alkaline hydrolysis that these glycosides are hexaosides of oleanolic acid and of hederagenin.
A MeOH extract from Z. africana was examined for topical antiinflammatory activity and proved to be active against arachidonic acid (AA) acute edema, 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced chronic inflammation, and oxazolone delayed-type hypersensitivity in mice. The extract also showed significant inhibitory activity of Naja naja phospholipase A2 when a polarographic method was used. Two oleanane-type triterpene saponins, zanhasaponins A (1) and B (2), and the cyclitol pinitol (4), isolated from the extract, were active as inhibitors of PLA2. A further saponin, zanhasaponin C (3) was inactive in this assay.
From the leaves of Hedera helix four new triterpenoid saponins, hederasaponins E [1], F [2], H [7], and I [8], and one known saponin (cauloside F) were isolated and characterized by chemical and spectroscopic methods.
α-Hederin, a saponin isolated from Hedera helix (L.) (Araliaceae), was tested on Candida albicans ultrastructure. The concentrations used were 6.25, 12.5, and 25 μg ml-1 for an exposure time of 24 h. Transmission electron microscopy observations indicated that compared with untreated control yeasts, α-hederin induced modifications of cellular contents and alterations of cell envelope with degradation and death of the yeasts. The impact of α-hederin on the biomembranes and in particular on the plasmalemma is discussed. The antifungal activity of α-hederin was confirmed, as was the minimal inhibitory concentration (25 μg ml-1). Zusammenfassung. α-Hederin, ein Saponin, gewonnen aus Hedera helix (L.) (Araliaceae), wurde in seiner Wirkung auf die Ultrastruktur von Candida albicans untersucht. Die eingesetzten Konzentrationen waren 6.25, 12.5 und 25 μ ml-1 bei einer Expositionsdauer von 24 h. Transmissionselektronenmikroskopische Untersuchungen zeigten α-Hederin-bedingte degradierende Veränderungen des Zellinhalts und der Zellwand, die zum Tod der Hefezellen führten. Die Bedeutung der α-Hederin-Wirkung auf die Biomembranen und insbesondere auf das Plasmalemma wird diskutiert. Die Minimale Hemmkonzentration MHK der antimyzetischen Aktivität des α-Hederins liegt bei 25 μg ml-1.
The effect of antidromic stimulation of the sensory fibres of the sciatic nerve on inflammatory plasma extravasation in various tissues and on cutaneous vasodilatation elicited in distant parts of the body was investigated in rats pretreated with guanethidine (8 mg kg ⁻¹ , i.p.) and pipecuronium (200 μg kg ⁻¹ , i.v.). Antidromic sciatic nerve stimulation with C‐fibre strength (20 V, 0.5 ms) at 5 Hz for 5 min elicited neurogenic inflammation in the innervated area and inhibited by 50.3±4.67% the development of a subsequent plasma extravasation in response to similar stimulation of the contralateral sciatic nerve. Stimulation at 0.5 Hz for 1 h also evoked local plasma extravasation and inhibited the carrageenin‐induced (1%, 100 μl s.c.) cutaneous inflammation by 38.5±10.0% in the contralateral paw. Excitation at 0.1 Hz for 4 h elicited no local plasma extravasation in the stimulated hindleg but still reduced the carrageenin‐induced oedema by 52.1±9.7% in the paw on the contralateral side. Plasma extravasation in the knee joint in response to carrageenin (2%, 200 μl intra‐articular injection) was diminished by 46.1±12.69% and 40.9±4.93% when the sciatic nerve was stimulated in the contralateral leg at 0.5 Hz for 1 h or 0.1 Hz for 4 h, respectively. Stimulation of the peripheral stump of the left vagal nerve (20 V, 1 ms, 8 Hz, 10 min) elicited plasma extravasation in the trachea, oesophagus and mediastinal connective tissue in rats pretreated with atropine (2 mg kg ⁻¹ , i.v.), guanethidine (8 mg kg ⁻¹ , i.p.) and pipecuronium (200 μg kg ⁻¹ , i.v.). These responses were inhibited by 37.8±5.1%, 49.7±9.9% and 37.6±4.2%, respectively by antidromic sciatic nerve excitation (5 Hz, 5 min) applied 5 min earlier. Pretreatment with polyclonal somatostatin antiserum (0.5 ml/rat, i.v.) or the selective somatostatin depleting agent cysteamine (280 mg kg ⁻¹ , s.c.) prevented the anti‐inflammatory effect of sciatic nerve stimulation (5 Hz, 5 min) on a subsequent neurogenic plasma extravasation of the contralateral paw skin. The inhibitory effect of antidromic sciatic nerve excitation on plasma extravasation in response to vagal nerve stimulation was also prevented by somatostatin antiserum pretreatment. Cutaneous blood flow assessment by laser Doppler flowmetry indicated that antidromic vasodilatation induced by sciatic nerve stimulation was not inhibited by excitation of the sciatic nerve of the contralateral leg (1 Hz, 30 min) or by somatostatin (10 μg/rat, i.v.) injection. Plasma levels of somatostatin increased more than 4 fold after stimulation of both sciatic nerves (5 Hz, 5 min) but the stimulus‐evoked increase was not observed in cysteamine (280 mg kg ⁻¹ , s.c.) pretreated rats. These results suggest that somatostatin released from the activated sensory nerve terminals mediates the systemic anti‐inflammatory effect evoked by stimulating the peripheral stump of the sciatic nerve. British Journal of Pharmacology (1998) 123 , 936–942; doi: 10.1038/sj.bjp.0701685
Antileishmanial activity is reported for the first time for saponins of ivy, Hedera helix L., in vitro on promastigote and amastigote forms of Leishmania infantum and Leishmania tropica. The compounds tested were an extract containing 60% of saponic complex (CS 60), the bidesmosides hederasaponin B, C, and D (saponin K10), their corresponding monodesmosides alpha-, beta-, and delta-hederin, and hederagenin. CS 60 and bidesmosides have shown no effect. Monodesmosides were found to be as effective on promastigote forms as the reference compound (pentamidine). Against amastigote forms only hederagenin exhibited a significant activity which was equivalent to that of the reference compound (N-methylglucamine antimonate).
Clonidine (0.1-1.0 mg/kg, i.p.) exhibited anti-inflammatory activity in carrageenan-, formalin-, 5-HT- and histamine-induced paw oedema in rats. Similarly, other two alpha 2-adrenoceptor agonists, guanfacine and B-HT 920, also displayed an anti-inflammatory action in these models. The anti-inflammatory effect of all the three alpha 2-adrenoceptor agonists was reversed by yohimbine. However, prazosin failed to block the anti-inflammatory effect of clonidine. Intracerebroventricularly administered clonidine had a delayed onset of anti-inflammatory action, starting only from 60 min post carrageenan administration. This was in contrast to the systemically administered clonidine which was effective against both phases of carrageenan-induced oedema. On the other hand, irrespective of the route of administration, i.e. peripheral or central, guanfacine and B-HT 920 were effective against the early as well as against the delayed phases of the inflammatory reaction. The studies suggest that it is not the imidazoline moiety but the activation of alpha 2-adrenoceptors which is essential for the anti-inflammatory action of these agents.
Administration of the mucopolysaccharide, carrageenan (CAR), into the hind paw of the rat or mouse induces a local inflammation characterized by increased arachidonic acid metabolism, increased vascular permeability, edema, and neutrophil extravasation. Carrageenan-induced hind-paw inflammation is inhibited by prostaglandin synthesis inhibitors, and this assay predicts the clinical success of anti-inflammatory agents in reducing peripheral inflammation. The purpose of this study was to determine if intraventricular injection of CAR would induce brain inflammation similar to that evoked by CAR in peripheral tissues. The present study demonstrates that CAR injection into the ventricles of the mouse brain does in fact induce an inflammatory response very similar to that caused by injection of CAR into the peripheral tissues. The brain response to CAR was dose-dependent, with the maximum increase in cerebrovascular permeability to iodine-125-labeled human serum albumin and percent brain water occurring after injection of 50 micrograms CAR. As is seen in CAR-induced inflammation of the hind paw, the maximum increase in brain vascular permeability occurred 4 hours after CAR injection. Histological analysis of brains 4 hours after CAR administration showed global neutrophil extravasation into the subarachnoid space and evidence of focal neuronal swelling. Methotrexate-induced neutropenia, however, failed to diminish the permeability response to CAR. Gas chromatographic and mass spectrometric measurements of brain prostaglandins 4 hours after CAR injection revealed a significantly increased level of 6-keto-prostaglandin F1 alpha. These results indicate that a significant increase in prostacyclin, the pro-inflammatory arachidonic acid metabolite, during CAR-induced brain inflammation is likely. These studies suggest that CAR-induced brain inflammation may be a useful model on which to test the efficacy of anti-inflammatory agents in the brain, as well as providing information concerning the mediators and mechanisms by which the brain may sustain inflammatory injury.