The cornel Iridoid glycoside attenuated brain edema of the cerebral ischemia/reperfusion rats by modulating the polarized aquaporin 4.

Brain edema after ischemic stroke could worsen cerebral injury in patients who received intravenous thrombolysis. Cornus officinalis Sieb. et Zucc., a long-established traditional Chinese medicine, is beneficial to the treatment of neurodegenerative diseases including ischemic stroke. In particular, its major component, cornel iridoid glycoside (CIG), was evidenced to exhibit neuroprotective effects against cerebral ischemic/reperfusion injury (CIR/I). Aimed to explore the effects of the CIG on brain edema of the CIR/I rats, the CIG was analyzed with the main constituents by using HPLC. The molecular docking analysis was performed between the CIG constituents and AQP4-M23. TGN-020, an AQP4 inhibitor, was used as a comparison. In the in vivo experiments, the rats were pre-treated with the CIG and were injured by performing middle cerebral artery occlusion/reperfusion (MCAO/R). After 24 h, the rats were examined for neurological function, pathological changes, brain edema, and polarized Aqp4 expressions in the brain. The HPLC analysis indicated that the CIG was composed of morroniside and loganin. The molecular docking analysis showed that both morroniside and loganin displayed lower binding energies to AQP4-M23 than TGN-020. The CIG pre-treated rats exhibited fewer neurological function deficits, minimized brain swelling, and reduced lesion volumes compared to the MCAO/R rats. In the peri-infarct and infarct regions, the CIG pre-treatment restored the polarized Aqp4 expression which was lost in the MCAO/R rats. The results suggested that the CIG could attenuate brain edema of the cerebral ischemia/reperfusion rats by modulating the polarized Aqp4 through the interaction of AQP4-M23 with morroniside and loganin.

seco-iridoid glycosides and flavonoid glycosides from the Gentiana olivieri Griseb and their anti-inflammatory activities.

Three undescribed seco-iridoid glycosides, one undescribed flavonoid glycoside, and three known glycosides were isolated and identified from Gentiana olivieri Griseb. The structures of these compounds were determined through spectroscopic analysis and ECD calculations. Olivierisecosides NP (1-3) were identified as aromatic conjugated seco-iridoid glucosides, among them olivierisecoside N was representing a particularly rare subtype known as the morroniside seco-iridoids. The compounds 2, 3, 5, and 6 exhibited significant inhibition of COX-2 expression, particularly compound 5 which demonstrated the most pronounced inhibitory activity with IC50 value of 23.33 ± 0.51 µM. This study provides evidence for the potential development and utilization of G. olivieri as a source of anti-inflammatory components.

Two new iridoid glycosides from the whole plant of Rehmania piasezkii.

Two new iridoid glycosides, piasezkiiosides A (1) and B (2), were isolated from aqueous extract of the whole plant of Rehmannia piasezkii. Their structures were established from the spectroscopic data, chemical transformation, and X-ray diffraction analysis. Compound 1 exhibited weak hepatoprotective activity against APAP-induced HepG2 cell damage.

Antinociceptive iridoid glycosides from the aerial parts of Paederia foetida.

Two previously undescribed iridoid glycosides, 6'-O-trans-feruloyl-(4S,6R)-3,4-dihydro-3ß-ethoxypaederoside (1) and 6'-O-trans-caffeoyl-(4S,6R)-3,4-dihydro-2'-O-3α-paederoside (2), were isolated from the 90% EtOH extract of the air dried aerial parts of Paederia Foetida. Structural elucidation of all the compounds was performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. The two isolated iridoid glycosides were tested in vivo for their antinociceptive properties. As a result, 2 showed potent antinociceptive effect and its ID50 value (53.4 µmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.

Bioactive neolignan, iridoid and flavonoid glycosides from the leaves of Vaccinium bracteatum.

Two neolignan glycosides including a new one (1), along with seven iridoid glycosides (3 - 9) and nine flavonoid glycosides (10 - 18), were isolated from the leaves of Vaccinium bracteatum. Their structures were established mainly on the basis of 1D/2D NMR and ESIMS analyses, as well as comparison to known compounds in the literature. The structure of 1 with absolute stereochemistry was also confirmed by chemical degradation and ECD calculation. Selective compounds showed antiradical activity against ABTS and/or DPPH. Moreover, several isolates also suppressed the production of ROS in RAW264.7 cells and exerted neuroprotective effect toward PC12 cells.

Leaves of Yellow Gentian (Gentiana lutea) as an Alternative Source of Bitter Secoiridoid Glycosides.

In a search for methods of manufacturing bitter principles from Gentiana lutea, mainly represented by gentiopicroside (1) and amarogentin (2), as an alternative to extraction from the roots of this plant, in this short communication it is shown that the leaves of this plant can be regarded as an additional source of such phytochemicals. Extraction of G. lutea leaves was coupled to solid-phase adsorption by differently structured solids as a separation technology step, providing a selective isolation of both these secondary metabolites in good to excellent yields. Thus, the extraction of bitter secoiridoids can be achieved in an equivalent or improved way rather than processing the roots of G. lutea while preserving the biodiversity of the species.

Six new secoiridoid glycosides from the stem barks of Syringa Reticulata (Bl.) Hara.

Six new secoiridoids, syrretosides E-J (1-6) and four known secoiridoids (7-10), were isolated from the stem barks of Syringa reticulata. Their structures were established by the 1D and 2D NMR spectra, HR-ESI-MS, and comparison with the literature. The cytotoxicity of the isolated monomeric compounds against RAW264.7 cells was investigated by the CCK8 assay, and the results showed that the individual compounds were not cytotoxic to RAW264.7. The anti-inflammatory activity of these compounds was evaluated using the LPS-induced RAW264.7 inflammatory cell model and the results showed that compounds 3-7 and 9 showed varying degrees of anti-inflammatory activity.

Antiviral iridoid glycosides from Clerodendrum myricoides.

The methanol root extract of Clerodendrum myricoides (Hochst.) Vatke afforded two new (1, 2) and two known (3, 4) iridoid glycosides. The structures of the isolated compounds were established based on NMR, IR, UV and MS data analyses. The crude extract and the isolated constituents were assayed for antiviral activity against the human respiratory syncytial virus (RSV) in human laryngeal epidermoid carcinoma (HEp-2) cells. The crude extract inhibited RSV infectivity at EC50 = 0.21 µg/ml, while it showed cytotoxicity against HEp-2 cells with CC50 = 9 µg/ml. Compound 2 showed 43.2% virus inhibition at 100 µM, while compounds 1 as well as 3 and 4 had only weak antiviral and cytotoxic activities.

Diagnostic ion filtering targeted screening and isolation of anti-inflammatory iridoid glycosides from Hedyotis diffusa.

Efficient and targeted screening and isolation of bioactive compounds from complex natural products is still a challenging work. Herein, diagnostic ion filtering based high-performance liquid chromatography-quadrupole time-of-flight-tandem mass spectrometry was firstly developed to screen six main iridoid glycosides from Hedyotis diffusa. Then, online extraction-high-speed counter current chromatography was proposed for targeted enrichment and preparative isolation using ethyl acetate/n-butanol/water (4.5:0.5:5, v/v/v) as solvent system. After that, Sephadex LH-20 column chromatography using methanol as solvent system was selected for further purification of six iridoid glycosides with purities over 98%. They were finally identified as monotropein, desacetylasperuloside acid, asperuloside, 6-O-(Z)-p-coumaroyl scandoside methyl ester, 6-O-(Z)-feruloyl scandoside methyl ester, and 6-O-(E)-p-coumaroyl scandoside methyl ester. And their anti-inflammatory activities were evaluated and confirmed by lipopolysaccharide activated RAW 264.7 macrophages. Obviously, the results provide a scientific basis for the potential applications of H. diffusa, and the developed methodology is efficient and reliable for targeted screening and isolation of bioactive compounds from natural products.

Two new iridoid glycosides from Gardeniae Fructus.

Two new iridoid glycosides, genipin 1,10-di-O-α-l-rhamnoside (1) and genipin 1,10-di-O-ß-d-xylopyranoside (2), along with thirteen known compounds (3-15) were isolated from Gardeniae Fructus. Their structures were elucidated by physical data analyses such as NMR, UV, IR, HR-ESI-MS, as well as chemical hydrolysis. All compounds were tested for their tyrosinase inhibitory and antioxidant activities. At a concentration of 25 µM, compound 13 showed obvious mushroom tyrosinase inhibition activity with % inhibition value of 36.52 ± 1.98%, with kojic acid used as the positive control (46.09 ± 1.29%). At a concentration of 1 mM, compounds 8 and 9 exhibited considerable DPPH radical scavenging activities, with radical scavenging rates of 48.54 ± 0.47%, 58.59 ± 0.39%, respectively, with l-ascorbic acid used as the positive control (59.02 ± 0.77%).

A new chlorine-containing iridoid glycoside from Plantago maxima.

A phytochemical investigation on the whole plant of Plantago maxima Juss. ex Jacq led to the isolation of a new and rare chlorinated iridoid glycoside named plantomoside (1), along with three known compounds, geniposidic acid (2), 10-deoxygeniposidic acid (3), and viteoid II (4). The structure of 1 was determined through 1 D and 2 D NMR spectroscopic data analysis, HR-ESI-MS, and acid hydrolysis.

Isolation of bioactive components with soluble epoxide hydrolase inhibitory activity from Stachys sieboldii MiQ. by ultrasonic-assisted extraction optimized using response surface methodology.

Stachys sieboldii MiQ (SSM) is an important food and medicinal herb in Korea, used to improve memory of patients with senile dementia and cardiovascular diseases. However, little information on bioactive components from SSM or standardized extraction methods for these components is available. This study isolated and purified major components from SSM for the first time, and assessed their ability to inhibit soluble epoxide hydrolase (sEH). The results showed that acteoside is the most potent inhibitor of sEH, with an IC50 of 33.5 ± 0.5 µM. Additional active components, including harpagide, tryptophan, and 8-acetate-harpagide, along with acteoside, were tentatively identified using high-performance liquid chromatography photodiode array tandem mass spectrometry (HPLC-PDA-MS/MS) and quantified using an ultraviolet detector at 210 nm. Further, an ultrasonic-assisted extraction technique for extraction of four bioactive compounds in SSM was developed and optimized using response surface methodology (RSM). The optimal extraction conditions were: extraction time, 30.46 minutes; extraction temperature, 67.95 °C, and methanol concentration 53.85%. The prediction model of RSM was validated with laboratory experiments. The similarity between predicted and actual values was 97.84%. The extraction method is thus a rapid, environment-friendly, energy-saving method can be applied to extract bioactive components from SSM in large quantities.

A new nitrogen-containing iridoid glycoside from lonicera macranthoides.

A new nitrogen-containing iridoid glycoside, named (7 R,3'R)-lonijapospiroside A (1), together with thirteen known iridoid glycosides, were isolated from the flower buds of Lonicera macranthoides. The structures of these compounds were established on the basis of spectroscopic analyses. Among them, compounds 1-4 are four diastereoisomers, and their absolute configurations were accurately established by the NOE spectra as well as comparison of their experimental and calculated ECD spectra. The anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on NO, IL-6, and TNF-α production in LPS stimulated RAW 264.7 macrophages. Compound 14 exhibited anti-inflammatory activities by inhibiting IL-6 with an IC50 value of 54.70 µM, comparable to that of the positive control (hydrocortisone, IC50: 62.6 ± 1.7 µM).

Protective effects of n-Butanol extract and iridoid glycosides of Veronica ciliata Fisch. Against ANIT-induced cholestatic liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Veronica ciliata Fisch. is a traditional medical herb that present in more than 100 types of Tibetan medicine prescriptions, most of which are used for liver disease therapy. Iridoid glycosides have been identified as the major active components of V.ciliata with a variety of biological activities. AIMS OF THE STUDY: The aim of this study is to explore the protective effect and potential mechanism of n-Butanol extract (BE) and iridoid glycosides (IG) from V.ciliata against ɑ-naphthyl isothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in mice. MATERIALS AND METHODS: Mice were intragastrically (i.g.) given BE and IG at different dose or positive control ursodeoxycholic acid (UCDA) once a day for 14 consecutive days, and were treated with ANIT to cause liver injury on day 12th. Serum levels of hepatic injury markers and cholestasis indicators, liver index and liver histopathology were measured to evaluate the effect of BE and IG on liver injury caused by ANIT. The protein levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B(NF-κB), interleukin-6 (IL-6), Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and the levels of oxidative stress indicators in liver tissue were investigated to reveal the underlying protective mechanisms of BE and IG against ANIT-induced hepatotoxicity and cholestasis. RESULTS: The n-Butanol extract (BE) and iridoid glycosides (IG) isolated from V.ciliata significantly decreased serum level of cholestatic liver injury markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL) in ANIT-treated mice. Histopathology of the liver tissue showed that pathological damages were relieved upon BE and IG treatment. Meanwhile, the results indicated BE and IG notably restored relative liver weights, inhibited oxidative stress induced by ANIT through increasing hepatic level of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and decreasing hepatic content of malondialdehyde (MDA). Western blot revealed that BE and IG inhibited the expression of pro-inflammatory factors TGF-α, IL-6 and NF-κB. Furthermore, the decreased protein expression of bile acid transporters NTCP, BSEP, MRP2 were upregulated by BE and IG in a dose-dependent manner. CONCLUSION: The results have demonstrated that BE and IG exhibited a dose-dependently protective effect against ANIT-induced liver injury with acute intrahepatic cholestasis in mice, which might be related to the regulation of oxidative stress, inflammatory response and bile acid transport. In addition, these findings pointed out that iridoid glycosides as main active components of V.ciliata play a critical role in hepatoprotective effect of V.ciliata.

Anti-rheumatoid arthritis effects of iridoid glucosides from Lamiophlomis rotata (Benth.) kudo on adjuvant-induced arthritis in rats by OPG/RANKL/NF-κB signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Lamiophlomisrotata (Benth.) Kudo. has been used to treat trauma bleeding, rheumatism, yellow water disease in traditional Chinese medicine. AIM: The aim of this work was to evaluate the anti-rheumatoid arthritis (RA) activities and underlying mechanisms of the total iridoid glucosides (TIG) from Lamiophlomisrotata (Benth.) Kudo. METHODS: The chemical constituents of TIG was analyzed by high-performance liquid chromatography (HPLC) with seven reference compounds (penstemonoside, chlorotuberside, shanzhiside methyl ester, phloyoside, 7-epliamalbide, phlorigidoside C and lamalbide). The anti-rheumatoid arthritis effects of TIG were investigated by arthritis indexes and paw swelling degrees, as well as histopathological and Micro-CT analysis in adjuvant-induced arthritis (AIA) rats. The impacts of TIG on the level of inflammatory cytokines (IL-1ß, TNF-α, IL-6, IFN-γ, IL-17 and IL-10), and the regulation of OPG/RANKL/NF-κB pathways were determined by the ELISA and western blot, respectively. RESULTS: TIG significantly reduced the arthritis indexes and paws swelling in AIA rats, attenuated the inflammation and bone destruction in joint tissues, reduced the generation of pro-inflammatory cytokines IL-1ß, TNF-α, IL-6, IFN-γ and IL-17, as well as increased the generation of anti-inflammatory cytokine IL-10 in serum. Moreover, TIG markedly inhibited the expression of p-IKK-α, p-IκB and p-p65, and decreased the ratio of OPG/RANKL in the synovial tissues. CONCLUSION: TIG possessed significant anti-RA activities on adjuvant-induced arthritis, which might be ascribed to the regulation of inflammatory cytokines IL-1ß, TNF-α, IL-6, IFN-γ IL-17 and IL-10, as well as inhibition of OPG/RANKL/NF-κB signaling pathways.

Harpagide: Occurrence in plants and biological activities - A review.

In this review article, the occurrence of harpagide in the plant kingdom and its associated biological activities are presented and detailed for the first time. The presence of harpagide has been reported in several botanical families within Asteridae, and harpagide has been observed to exert a wide number of biological activities such as cytotoxic, anti-inflammatory, and neuroprotective. These results show how harpagide can be recovered from several natural sources for several pharmacological purposes even if there is a lot to still be studied. Nowadays, the interest is related to its presence in phytomedicines. Threfore, these studies are useful to support and validate the large use of several plants in the folklore medicine.

Collagen synthesis-promoting and collagenase inhibitory activities of constituents isolated from the rhizomes of Picrorhiza kurroa Royle ex Benth.

Three new acylated phenylethanoid glycosides, kurroaosides A (14), B (15), and C (16), and a new acylated cucurbitane-type triterpene glycoside, kurroaoside D (17), were isolated from a methanol extract of the rhizomes of Picrorhiza kurroa Royle ex Benth. (Plantaginaceae) along with 29 known isolates including 10 acylated phenylethanoid glycosides (18-27), three cucurbitane-type triterpene glycosides (32-34), and a nortriterpene glycoside (35). The structures of these new compounds (14-17), including their stereochemistry, were determined based on chemical and physicochemical evidence derived from NMR and MS analysis. Among the isolates, acylated iridoid glycosides, picrosides I (8), II (9), III (10), and IV (11) and 6-feruloylcatalpol (12), phenylethanoid glycosides (14-16), triterpene glycosides, cucurbitacin B 2-O-ß-D-glucopyranoside (32) and 25-acetoxy-2-ß-D-glucopyranosyloxy-3,16,20-trihydroxy-9-methyl-19-norlanosta-5-en-22-one (35), and an acetophenone glycoside, picein (36), significantly promoted collagen synthesis at 10-30 µM, with no cytotoxicity being observed at the effective concentrations. Furthermore, acylated phenylethanoid glycosides, calceolarioside A (19, IC50 = 69.2 µM), plantamajoside (20, 51.8 µM), isoplantamajoside (21, 76.8 µM), and scroside E (23, 65.5 µM), exhibited collagenase inhibitory activity equivalent to that of positive agents caffeic acid (75.6 µM) and epigallocatechin 3-O-gallate (75.4 µM).

Characterization, crystal structure and cytotoxic activity of a rare iridoid glycoside from Lonicera saccata.

A new iridoid glycoside, methyl (3R,4R,4aS,7S,7aR)-3-hydroxy-7-methyl-5-oxooctahydrocyclopenta[c]pyran-4-carboxylate-3-O-ß-D-(1'S,2'R,3'S,4'S,5'R)-glucopyranoside, named loniceroside A, C17H26O10, (1), was obtained from the aerial parts of Lonicera saccata. Its structure was established based on an analysis of spectroscopic data, including 1D NMR, 2D NMR and HRESIMS, and the configurations of the chiral C atoms were determined by X-ray crystallographic analysis. The single-crystal structure reveals that the cyclopenta[c]pyran scaffold is formed from a five-membered ring and a chair-like six-membered ring connected through two bridgehead chiral C atoms. In the solid state, the glucose group of (1) plays an important role in constructing an unusual supramolecular motif. The structure analysis revealed adjacent molecules linked together through intermolecular O-H...O hydrogen bonds to generate a banded structure. Furthermore, the banded structures are linked into a three-dimensional network by interesting hydrogen bonds. Biogenetically, compound (1) carries a glucopyranosyloxy moiety at the C-3 position, representing a rare structural feature for naturally occurring iridoid glycosides. The growth inhibitory effects against human cervical carcinoma cells (Hela), human lung adenocarcinoma cells (A549), human acute mononuclear granulocyte leukaemia (THP-1) and the human liver hepatocellular carcinoma cell line (HepG2) were evaluated by the MTT method.

Harpagide from Scrophularia protects rat cortical neurons from oxygen-glucose deprivation and reoxygenation-induced injury by decreasing endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Harpagide is the main ingredient in Scrophularia ningpoensis Hemsl which is used for the therapeutic purpose of treating encephalopathy. Harpagide has shown promise in the treatment of oxygen-glucose deprivation and reoxygenation (OGD/R)-induced brain injury. However, the underlying mechanisms remain unclear. AIM OF STUDY: In this study, we aimed to determine the neuroprotective effect of harpagide on rat cortical neurons under OGD/R conditions that induce the development of ischaemia-reperfusion (I/R). MATERIALS AND METHODS: To explore the biological function of harpagide in cerebral ischaemia-reperfusion injury (CIRI), The CIRI model was established by oxygen-glucose deprivation and reoxygenation (OGD/R) on rat cortical neurons. It tested cell survival rate by 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, apoptosis by flow cytometry, intracellular Ca2+ concentration [Ca2+] i by cofocal laser, and expressions related to endoplasmic reticulum stress (ERS) by RT-PCR and Western blot. RESULTS: We found that pretreatment with harpagide (50 µM) prevented OGD/R-induced apoptotic cell death. Harpagide also significantly decreased the gene expression levels and protein production of ERS-related proteins. We found that harpagide also exerted a neuroprotective effect on TG-induced apoptosis in rat cortical neurons and decreased the gene expression levels and protein production of GRP78, caspase-12 and CHOP. We also measured the intracellular calcium ion concentration ([Ca2+]i) in neurons and found that harpagide significantly decreased the [Ca2+]i induced by OGD/R and TG. CONCLUSION: These results suggest that harpagide protects against OGD/R-induced cell apoptosis, likely by decreasing ERS. Collectively, harpagide was demonstrated to be a prominent suppressor of ERS and prevented the apoptosis of rat cortical neurons. Based on the results, harpagide could potentially serve as a therapeutic agent of ischaemia-like injury associated with excessive ERS and apoptosis.

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication.

Epidemic and pandemic influenza A virus (IAV) poses a significant threat to human populations worldwide. Iridoid glycosides are principal bioactive components from the Gardenia jasminoides J. Ellis fruit that exhibit antiviral activity against several strains of IAV. In the present study, we evaluated the protective effect of Fructus Gardeniae iridoid glycoside extracts (IGEs) against IAV by cytopathogenic effect(CPE), MTT and a plaque formation assay in vitro and examined the reduction in the pulmonary index (PI), restoration of body weight, reduction in mortality and increases in survival time in vivo. As a host factor, PACT provides protection against the pathogenic influenza A virus by interacting with IAV polymerase and activating the IFN-I response. To verify the whether IGEs suppress IAV replication in a PACT-dependent manner, IAV RNA replication, expression of PACT and the phosphorylation of eIF2α in A549 cells were detected; the levels of IFNß, PACT and PKR in mouse lung tissues were determined; and the activity of IAV polymerase was evaluated in PACT-compromised cells. The results indicated that IGEs sufficiently alleviated cell damage and suppressed IAV replication in vitro, protecting mice from IAV-induced injury and lethal IAV infection. These anti-IAV effects might be related to disrupted interplay between IVA polymerase and PACT and/or prevention of a PACT-dependent overactivated IFN-I antiviral response. Taken together, our findings reveal a new facet of the mechanisms by which IGEs fight the influenza A virus in a PACT-dependent manner.