Total iridoid glycoside extract of Lamiophlomis rotata (Benth) Kudo accelerates diabetic wound healing by the NRF2/COX2 axis.

BACKGROUND: Lamiophlomis rotata (Benth.) Kudo (L. rotata), the oral Traditional Tibetan herbal medicine, is adopted for treating knife and gun wounds for a long time. As previously demonstrated, total iridoid glycoside extract of L. rotata (IGLR) induced polarization of M2 macrophage to speed up wound healing. In diabetic wounds, high levels inflammatory and chemotactic factors are usually related to high reactive oxygen species (ROS) levels. As a ROS target gene, nuclear factor erythroid 2-related factor 2 (NRF2), influences the differentiation of monocytes to M1/M2 macrophages. Fortunately, iridoid glycosides are naturally occurring active compounds that can be used as the oxygen radical scavenger. Nevertheless, the influence of IGLR in diabetic wound healing and its associated mechanism is largely unclear. MATERIALS AND METHODS: With macrophages and dermal fibroblasts in vitro, as well as a thickness excision model of db/db mouse in vivo, the role of IGLR in diabetic wound healing and the probable mechanism of the action were investigated. RESULTS: Our results showed that IGLR suppressed oxidative distress and inflammation partly through the NRF2/cyclooxygenase2 (COX2) signaling pathway in vitro. The intercellular communication between macrophages and dermal fibroblasts was investigated by the conditioned medium (CM) of IGLR treatment cells. The CM increased the transcription and translation of collagen I (COL1A1) and alpha smooth muscle actin (α-SMA) within fibroblasts. With diabetic wound mice, the data demonstrated IGLR activated the NRF2/KEAP1 signaling and the downstream targets of the pathway, inhibited COX2/PEG2 signaling and decreased the interaction inflammatory targets of the axis, like interleukin-1beta (IL-1ß), interleukin 6 (IL-6), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase1 (caspase1) and NOD-like receptor-containing protein 3 (NLRP3).In addition, the deposition of COL1A1, and the level of α-SMA, and Transforming growth factor-ß1 (TGF-ß1) obviously elevated, whereas that of pro-inflammatory factors reduced in the diabetic wound tissue with IGLR treatment. CONCLUSION: IGLR suppressed oxidative distress and inflammation mainly through NRF2/COX2 axis, thus promoting paracrine and accelerating wound healing in diabetes mice.

Bioactivities of morroniside: A comprehensive review of pharmacological properties and molecular mechanisms.

Morroniside (MOR) is an iridoid glycoside and the main active principle of the medicinal plant, Cornus officinalis Sieb. This phytochemical is associated with numerous health benefits due to its antioxidant properties. The primary objective of the present study was to assess the pharmacological effects and underlying mechanisms of MOR, utilizing published data obtained from literature databases. Data collection involved accessing various sources, including PubMed/Medline, Scopus, Science Direct, Google Scholar, Web of Science, and SpringerLink. Our findings demonstrate that MOR can be utilized for the treatment of several diseases and disorders, as numerous studies have revealed its significant therapeutic activities. These activities encompass anti-inflammatory, antidiabetic, lipid-lowering capability, anticancer, trichogenic, hepatoprotective, gastroprotective, osteoprotective, renoprotective, and cardioprotective effects. MOR has also shown promising benefits against various neurological ailments, including Alzheimer's disease, Parkinson's disease, spinal cord injury, cerebral ischemia, and neuropathic pain. Considering these therapeutic features, MOR holds promise as a lead compound for the treatment of various ailments and disorders. However, further comprehensive preclinical and clinical trials are required to establish MOR as an effective and reliable therapeutic agent.

Hepatoprotective Principles from the Rhizomes of Picrorhiza kurroa.

A methanol extract of rhizomes of Picrorhiza kurroa Royle ex Benth. (Plantaginaceae) showed hepatoprotective effects against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. We had previously isolated 46 compounds, including several types of iridoid glycosides, phenylethanoid glycosides, and aromatics, etc., from the extract. Among them, picroside II, androsin, and 4-hydroxy-3-methoxyacetophenone exhibited active hepatoprotective effects at doses of 50-100 mg/kg, per os (p.o.) To characterize the mechanisms of action of these isolates and to clarify the structural requirements of phenylethanoid glycosides for their hepatoprotective effects, their effects were assessed in in vitro studies on (i) D-GalN-induced cytotoxicity in mouse primary hepatocytes, (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages, and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. These isolates decreased the cytotoxicity caused by D-GalN without inhibiting LPS-induced macrophage activation and also reduced the sensitivity of hepatocytes to TNF-α. In addition, the structural requirements of phenylethanoids for the protective effects of D-GalN-induced cytotoxicity in mouse primary hepatocytes were evaluated.

The total iridoid glycoside extract of Lamiophlomis rotata Kudo induces M2 macrophage polarization to accelerate wound healing by RAS/ p38 MAPK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Lamiophlomis rotata (Benth.) Kudo (L. rotata), a Tibetan medicinal plant, is used to treat "yellow-water diseases", such as skin disease, jaundice and rheumatism. Our previous study showed that the iridoid glycoside extract of L. rotata (IGLR) is the major constituent of skin wound healing. However, the role of IGLR in the biological process of trauma repair and the probable mechanism of the action remain largely unknown. AIM OF THE STUDY: To investigate the role of IGLR in the biological process of trauma repair and the probable mechanism of the action. MATERIALS AND METHODS: The role of IGLR in wound healing was investigated by overall skin wound in mice with Hematoxylin and Eosin (H&E) and Masson trichrome staining. The anti-inflammatory, angiogenesis-promoting and fibril formation effects of IGLR were visualized in wound skin tissue by immunofluorescence staining, and the proinflammatory factors and growth factors were assayed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Macrophages, dermal fibroblasts, and endothelial cells were cultured to measure the direct/indirect interaction effects of IGLR on the proliferation and migration of cells, and flow cytometry was employed to assess the role of IGLR on macrophage phenotype. Network pharmacology combined with Western blot experiments were conducted to explore possible mechanisms of the actions. RESULTS: IGLR increased the expression of CD206 (M2 markers) through the RAS/p38 MAPK/NF-κB signaling pathway during wound injury in vivo and in vitro. IGLR suppressed the inflammatory cytokines iNOS, IL-1ß and TNF-α in the early stage of wound healing. During the proliferation step of wound repair, IGLR promoted angiogenesis and fibril formation by increasing the expression of VEGF, CD31, TGF-ß and α-SMA in wound tissue, and similar results were verified by RT-PCR and ELISA. In a paracrine mechanism, the extract promoted the proliferation of dermal fibroblasts, and endothelial cells were founded by the conditioned medium (CM). CONCLUSION: IGLR induced M2 macrophage polarization in the early stage of wound healing; in turn, IGLR played a key role in the transition from inflammation to cell proliferation during the biological process of wound healing.

Four new terpenoids and other metabolites with potential anti-complementary activities from the aerial parts of Dracocephalum moldavica (Lamiaceae).

In the course of our continuing search for biologically active compounds from medicinal herbs, four undescribed terpenoids including one monoterpenoid glycoside, (1 R, 3S, 4S, 5 R)-(-)-1,8-epoxy-p-menthan-5-ethoxycarbonyl-3-O-ß-D-glucopyranoside (1), one iridoid glycoside, 3'-O-ß-D-glucopyranosyl-melampyroside (2), one sesquiterpene, 1-(2-methylbutanol)-2-pentyl-1,3-cyclohexadiene (3), and one triterpenoid, 28-nor-3ß,18ß-dihydroxyurs-12-ene (4), together with nine known terpenoids (5-13) were isolated from the dried aerial parts of Dracocephalum moldavica (Lamiaceae). Their chemical structures were elucidated by detailed spectroscopy (1 D and 2 D NMR), HRESIMS data analysis and acid hydrolysis. Among them, compounds 9 and 10 were isolated from the family Lamiaceae, compounds 5, 6 and 11-13 were identified from the genus Dracocephalum and compounds 7 and 8 were reported from the D. moldavica for the first time. The biological evaluation of anti-complementary activity revealed that some compounds, 4, 6 and 12 exhibited anti-complementary activity with CH50 and AP50 values ranging from 0.67-1.43 and 1.12-1.55 mM, respectively.

Isolation of phytochemicals from Dolichandrone atrovirens followed by semisynthetic modification of ixoside via azomethine ylide cycloaddition; computational approach towards chemo-selection.

Aims of the study were the phytochemical investigation and chemical transformation of isolated compounds of medicinal plant listed in 'Ayurveda' like Dolichandrone atrovirens, endemic to Indian subcontinents. From chloroform extract of D. atrovirens four compounds; Ursolic acid (1), Maslinic acid (2), Lupeol (3), ß-sitosterol (4) and from methanol extract five compounds; ß-sitosterol-3-O-ß-D-glucopyranoside (5), 10-O-trans-p-Methoxycinnamoylcatalpol (6), Kaempferol-3-O-ß-D-glucopyranoside (7), 6-O-[6"(S)-hydroxy-2",6"dimethyl-2"(E)-7"-octadienoyl] catalpol (8) and Ixoside (9) were isolated. Ixoside was used for the semi-synthetic modification via azomethine ylide cycloaddition leading to novel spiro-oxindolo-pyrrolizidine adduct. The structures of novel adducts were elucidated by analysis of IR, MS and 1 D/2D NMR data. Furthermore, to confirm the chemo selection of only one double bond, we performed density functional theory (DFT) calculation, which confirms the chemo selectivity. In addition, in-silico ADME studies and atom-additive approach based on SASA was also examined for the molecules which suggest that they may be potential future candidates for drug discovery.

Two new iridoid glycosides from Hedyotis diffusa.

Two new iridoid glycosides, named productasperulosidic acid butyl ester (1) and E-6-O-3-hydroxy-p-methoxycinnamoyl scandoside methyl ester (2), along with nine known ones (3-11), were isolated from Hedyotis diffusa Willd. The structures of them were elucidated by extensive 1D, 2D NMR and HR-ESI-MS spectral data. Compounds 1-11 showed no significant cytotoxic activity against HeLa cells.

Distribution profile of iridoid glycosides and phenolic compounds in two Barleria species and their correlation with antioxidant and antibacterial activity.

Introduction: Barleria prionitis is known for its medicinal properties from ancient times. Bioactive iridoid glycosides and phenolic compounds have been isolated from leaves of this plant. However, other parts of a medicinal plants are also important, especially roots. Therefore, it is important to screen all organs for complete chemical characterization. Method: All parts of B. prionitis, including leaf, root, stem and inflorescence in search of bioactive compounds, with a rapid and effective metabolomic method. X500R QTOF system with information dependent acquisition (IDA) method was used to collect high resolution accurate mass data (HRMS) on both the parent (MS signal) and their fragment ions (MS/MS signal). ESI spectra was obtained in positive ion mode from all parts of the plant. A comparative analysis of antioxidant and antibacterial activity was done and their correlation study with the identified compounds was demonstrated. Principal component analysis was performed. Result: Iridoid glycosides and phenolic compounds were identified from all parts of the showing variability in presence and abundance. Many of the compounds are reported first time in B. prionitis. Antioxidant and antibacterial activity was revealed in all organs, root being the most effective one. Some of the iridoid glycoside and phenolic compounds found to be positively correlated with the tested biological activity. Principal component analysis of the chemical profiles showed variability in distribution of the compounds. Conclusion: All parts of B. prionitis are rich source of bioactive iridoid glycosides and phenolic compounds.

Secondary metabolites from Valeriana jatamansi with their anti-inflammatory activity.

Valeriana jatamansi is hired as multiple remedies for treatment of insomnia, blood and circulatory disorders, asthma, dry cough, jaundice, seminal weakness, cardiac debility, and skin diseases in Vietnam. Our research discovered the phytochemical investigation of constituents from this herbal medicine resulted in the isolation of two new compounds (jatamansides A (4) and B (7)) together with 16 known ones from the whole plant. Their structures were established by using spectroscopic techniques (multinuclear and multidimensional nuclear magnetic resonance, infrared, ultraviolet-visible), mass spectrometry, hydrolysis analysis, or comparing their NMR data to those reported in the literature. In addition, all the isolates were evaluated for their inhibitory effect against TNF-α production in LPS-stimulated on RAW264.7 cells with significant inhibition.

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.

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.

Pterocephanoside A, a new iridoid from a traditional Tibetan medicine, Pterocephalus hookeri.

This work obtained and identified pterocephanoside A (1), one new iridoid glucoside derivative with rare structure of three iridoid glycosides linked to cyclopenta[c]pyran-3(1H)-one, and 10 known iridoids (2-11) from Pterocephalus hookeri through silica gel column chromatography and semi-preparative HPLC. The structure of the new compound was confirmed by 1D and 2D NMR and HRMS data analysis. Compounds 1 and 2 were isolated from this plant for the first time. The iridoids mostly possessed seco-iridoid subtype and iridoid subtype skeletons from P. hookeri. Compounds 1, 3, 4, and 6-11 showed weak anti-inflammatory activity.

Bioassay-Guided Isolation of Anti-Alzheimer Active Components from the Aerial Parts of Hedyotis diffusa and Simultaneous Analysis for Marker Compounds.

Previous studies have reported that Hedyotis diffusa Willdenow extract shows various biological activities on cerebropathia, such as neuroprotection and short-term memory enhancement. However, there has been a lack of studies on the inhibitory activity on neurodegenerative diseases such as Alzheimer's disease (AD) through enzyme assays of H. diffusa. Therefore, H. diffusa extract and fractions were evaluated for their inhibitory effects through assays of enzymes related to AD, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), and on the formation of advanced glycation end-product (AGE). In this study, ten bioactive compounds, including nine iridoid glycosides 1-9 and one flavonol glycoside 10, were isolated from the ethyl acetate and n-butanol fractions of H. diffusa using a bioassay-guided approach. Compound 10 was the strongest inhibitor of cholinesterase, BACE1, and the formation of AGEs of all isolated compounds, while compound 5 had the lowest inhibitory activity. Compounds 3, 6, and 9 exhibited better inhibitory activity than other compounds on AChE, and two pairs of diastereomeric iridoid glycoside structures (compounds 4, 8, and 6, 7) showed higher inhibitory activity than others on BChE. In the BACE1 inhibitory assay, compounds 1-3 were good inhibitors, and compound 10 showed higher inhibitory activity than quercetin, the positive control. Moreover, compounds 1 and 3 were stronger inhibitors of the formation of AGE than aminoguanidine (AMG), the positive control. In conclusion, this study is significant since it demonstrated that the potential inhibitory activity of H. diffusa on enzymes related to AD and showed the potential use for further study as a natural medicine for AD treatment on the basis of the bioactive components isolated from H. diffusa.

Iridoid glycosides from Morinda officinalis How. exert anti-inflammatory and anti-arthritic effects through inactivating MAPK and NF-κB signaling pathways.

BACKGROUND: The root of Morinda officinalis How. (MO, the family of Rubiaceae) has long been used to treat inflammatory diseases in China and other eastern Asian countries, and iridoid glycosides extracted from MO (MOIG) are believed to contribute to this anti-inflammatory effect. However, the mechanism underlying the anti-inflammatory and anti-arthritic activities of MOIG has not been elucidated. The aim of the present study was to determine how MOIG exerted anti-inflammatory and anti-arthritic effects in vivo and in RAW 264.7 macrophages. METHODS: MOIG were enriched by XDA-1 macroporous resin. The maximum feasible dose method was adopted to evaluate its acute toxicity. The analgesic effect of MOIG was evaluated by acetic acid writhing test and the anti-inflammatory effect was evaluated by cotton-pellet granuloma test in rats and air pouch granuloma test in mice. The anti-arthritic effect was evaluated by establishing an adjuvant arthritis model induced by Complete Freund's Adjuvant (CFA). The viability of the cultured RAW 264.7 macrophages was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The anti-inflammatory activity was evaluated by measuring NO, IL-1ß, IL-6 and TNF-α levels in LPS-stimulated RAW 264.7 cells. The protein level of inflammatory responsive genes was evaluated by Western blot analysis. RESULTS: MOIG had no significant toxicity at maximum feasible dose of 22.5 g/kg. MO extracts and MOIG (50,100 and 200 mg/kg) all evoked a significantly inhibitory effects on the frequency of twisting induced by acetic acid in mice compared with the model control group. Administration of MO extracts and MOIG markedly decreased the dry and wet weight of cotton pellet granuloma in rats and air pouch granuloma in mice. MOIG significantly attenuated the paw swelling and decreased the arthritic score, weight loss, spleen index, and the serum level of inflammatory factors IL-1ß, IL-6 and IL-17a in CFA-induced arthritic rats. MOIG inhibited the production of inflammatory cytokines in LPS-stimulated RAW264.7 cells, and the expressions of iNOS, COX-2 and proteins related to MAPK and NF-κB signaling pathways in LPS-stimulated RAW 264.7 macrophages. CONCLUSION: MOIG exerted anti-inflammatory and anti-arthritic activities through inactivating MAPK and NF-κB signaling pathways, and this finding may provide a sound experimental basis for the clinical treatment of rheumatoid arthritis with MOIG.

Prediction the contents of fructose, glucose, sucrose, fructo-oligosaccharides and iridoid glycosides in Morinda officinalis radix using near-infrared spectroscopy.

Morindae officinalis radix (MOR) is a famous Chinese herbal medicine which has long history of use in medicine and food. MOR and MOR with steaming process (PMOR) are the most commonly used forms in in clinical and health care. In order to establish a fast and mostly nondestructive quality control method for MOR, 183 beaches of MOR samples and 20 beaches of PMOR samples were collected commercially from major producing areas in Guangdong, Fujian and Guangxi Provinces of China. To predict main components of MOR, a calibration model was established based on near-infrared spectroscopy with partial least square regression. The model was optimized by compared the parameters of root mean square error of prediction (RMSEP), root mean square error of cross validation (RMSECV), coefficient of correlation (R2) and ratio of performance to deviation (RPD). Comparative studies were performed to evaluate the performance of models by different spectra preprocessing methods and different data set. The results showed that the model performance was improved with standard normal variate spectra preprocessing methods and when the data set contained both MOR and PMOR samples. A few PMOR samples were added to MOR samples data set the model predictive performance could be improved. The contents of 14 components were predicted in MOR with lower RMSEP and RMSECV, and higher R2 and RPD, including fructose (12.8 mg/g, 16.3 mg/g, 0.9873, 10.10), glucose (7.28 mg/g, 8.73 mg/g, 0.9611, 6.21 sucrose (9.24 mg/g, 9.10 mg/g, 0.8419, 1.75), GF2(9.42 mg/g, 11.3 mg/g, 0.8526, 2.03), GF3(7.98 mg/g, 9.20 mg/g, 0.8756, 2.74), GF4(6.81 mg/g, 8.93 mg/g, 0.8663, 3.06), GF5(8.13 mg/g, 8.85 mg/g, 0.9001, 3.06), GF6(6.40 mg/g, 6.95 mg/g, 0.9145, 3.27), GF7(5.53 mg/g, 6.15 mg/g, 0.9195, 3.57), GF8(5.40 mg/g, 6.02 mg/g, 0.9179, 3.31), GF9(3.00 mg/g,4.35 mg/g,0.9446, 5.03),GF10(4.08 mg/g, 5.34 mg/g, 0.8983, 3.62), GF11(8.97 mg/g, 7.70 mg/g, 0.8683, 2.01) and iridoid glycosides (4.12 mg/g, 5.51 mg/g, 0.8712, 2.43). The model established in this paper could predict 14 components of MOR. The results would provide a reference method for the quality control of Chinese medical materials and their process products.

Iridoid, phenylethanoid and flavonoid glycosides from Forsythia suspensa.

As part of our continuing efforts to explore bioactive compounds from natural resources, a new iridoid glycoside, adoxosidic acid-6'-oleuroperic ester (1), together with one known phenylethanoid glycoside (2) and two known flavonoid glycosides (3-4) were isolated from the fruit of Forsythia suspensa. The structure of the new compound (1) was elucidated through 1D and 2D NMR spectroscopic data and HR-ESIMS. Interestingly, compound 1 was a monoterpene ester of one iridoid glycoside. Compounds 2-4 were identified as calceolarioside A (2), kaempferol-3-O-rutinoside (3), kampferol-3-O-robinobioside (4) on the basis of NMR spectroscopic data analyses and comparison with the data reported in the literature. The antiviral activity aganisist influenza A (H5N1) virus of compound 1 was studied as well.

Cornel Iridoid Glycoside Suppresses Hyperactivity Phenotype in rTg4510 Mice through Reducing Tau Pathology and Improving Synaptic Dysfunction.

rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer's disease (AD). Besides cognitive impairments, rTg4510 mice also show abnormal hyperactivity behavior. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity, and related mechanisms. The emotional hyperactivity was detected by locomotor activity test and Y maze test. Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau. Western blotting was used to detect the expression of related proteins. The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype, prevented neuronal loss, reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice. Meanwhile, CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors (NMDARs) subunits GluN1 and GluN2A and αamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunits GluA1 and GluA2, and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase II α (p-CaMK IIα) in the brain of rTg4510 mice. In conclusion, CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.

Cornel iridoid glycoside induces autophagy to protect against tau oligomer neurotoxicity induced by the activation of glycogen synthase kinase-3ß.

Tau oligomers are the etiologic molecules of Alzheimer's disease, and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic aggregate species. The aim of the present study was to investigate the mechanisms of cornel iridoid glycoside (CIG) on tau oligomers and cognitive functions. We injected wortmannin and GF-109203X (WM/GFX, 200 µM each) into the lateral ventricles to induce tau oligomer and memory impairment in rats. When orally administered with CIG at 60 and 120 mg/kg/day for 14 days, CIG decreased the escape latency in the Morris water maze test. We also found that CIG restored the expression of presynaptic p-synapsin, synaptophysin, and postsynaptic density-95 (PSD-95) decreased by WM/GFX in rat cortex. CIG reduced the accumulation of tau oligomers in the brain of WM/GFX rats and in cells transfected with wild type glycogen synthase kinase-3ß (wtGSK-3ß). In addition, CIG up-regulated the levels of ATG7, ATG12, Beclin-1, and LC3II in vivo and in vitro, suggesting the restoration of autophagy function. These results suggest that CIG could ameliorate memory deficits and regulate memory-associated synaptic proteins through the clearance of tau oligomers accumulation. Moreover, CIG clears tau oligomers by restoring autophagy function.

Cornel Iridoid Glycoside Suppresses Tau Hyperphosphorylation and Aggregation in a Mouse Model of Tauopathy through Increasing Activity of PP2A.

BACKGROUND: rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathy including Alzheimer's Disease (AD). Cornel Iridoid Glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on tau pathology and underlying mechanisms using rTg4510 mice. METHODS: The cognitive functions were detected by Morris water maze and objective recognition tests. Western blotting and immunofluorescence were conducted to measure the levels of phosphorylated tau and related proteins. Serine/threonine phosphatase assay was applied to detect the activity of protein phosphatase 2A (PP2A). RESULTS: Intragastric administration of CIG for 3 months improved learning and memory abilities, prevented neuronal and synapse loss, halted brain atrophy, elevated levels of synaptic proteins, protected cytoskeleton, reduced tau hyperphosphorylation and aggregation in the brain of rTg4510 mice. In the mechanism studies, CIG increased the activity of PP2A, elevated the methylation of PP2A catalytic C (PP2Ac) at leucine 309, decreased the phosphorylation of PP2Ac at tyrosine 307, and increased protein expression of leucine carboxyl methyltransferase 1 (LCMT-1), protein tyrosine phosphatase 1B (PTP1B), and protein phosphatase 2A phosphatase activator (PTPA) in the brain of rTg4510 mice. CONCLUSION: CIG might have the potential to treat tauopathy such as AD via activating PP2A.

A syringic acid derivative and two iridoid glycosides from the roots of Stachys geobombycis and their antioxidant properties.

A new derivative of syringic acid, stageobester A (1) and two iridoid glycosides which including a new one, stageoboside A (2), were isolated from the roots of Stachys geobombycis. Their structures were elucidated on the basis of spectroscopic methods, including extensive NMR and MS spectra. In addition, all the isolates were tested for their antioxidant capacity. Compounds 1 and 2 showed moderate antioxidant activities against DPPH radical, with IC50 values of 113.33 ± 1.53 and 40.33 ± 2.08 mg/L, respectively.