iridoids and acevaltrate

Cytotoxic activity-guided isolation studies on the underground parts of Valeriana sisymbriifolia Vahl. led to the isolation of 12 secondary metabolites including two undescribed iridoids, sisymbriifolivaltrate and sisymbriifolioside, and two unreported sesquiterpene lactones, sisymbriifolins A and B. Chemical structures of the isolates were established by extensive 1D and 2D NMR analyses as well as HR-ESI-MS. The in vitro cytotoxic activities of the extract, sub-fractions and isolates on lung (A549), breast (MCF7), gastric (HGC27) and prostate (PC3) cancer cell lines were evaluated by MTS assay. Sisymbriifolivaltrate, didrovaltrate, valtrate, 7-homovaltrate and 1-α-acevaltrate exhibited promising cytotoxic activity on MCF7 cell line with IC

Topics: Animals; Antineoplastic Agents; Iridoids; Valerian

Recent studies show that the expression of CCND1, a key factor in cell cycle control, is increased following the progress and deteriotation of glioma and predicts poor outcomes. On the other hand, dysregulated deubiquitinase USP10 also predicts poor prognosis for patients with glioblastoma (GBM). In the present study, we investigated the interplay between CCND1 protein and USP10 in GBM cells. We showed that the expression of CCND1 was significantly higher in both GBM tissues and GBM-derived stem cells. USP10 interacted with CCND1 and prevented its K48- but not K63-linked polyubiquitination in GBM U251 and HS683 cells, which led to increased CCND1 stability. Consistent with the action of USP10 on CCND1, knockdown of USP10 by single-guided RNA downregulated CCND1 and caused GBM cell cycle arrest at the G1 phase and induced GBM cell apoptosis. To implement this finding in the treatment of GBMs, we screened a natural product library and found that acevaltrate (AVT), an active component derived from the herbal plant Valeriana jatamansi Jones was strikingly potent to induce GBM cell apoptosis, which was confirmed by the Annexin V staining and activation of the apoptotic signals. Furthermore, we revealed that AVT concentration-dependently suppressed USP10-mediated deubiquitination on CCND1 therefore inducing CCND1 protein degradation. Collectively, the present study demonstrates that the USP10/CCND1 axis could be a promising therapeutic target for patients with GBMs.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Glioblastoma; HEK293 Cells; Humans; Iridoids; Ubiquitin Thiolesterase; Ubiquitination

The oncogenic transcript factor c-Maf is stabilized by the deubiquitinase Otub1 and promotes myeloma cell proliferation and confers to chemoresistance. Inhibition of the Otub1/c-Maf axis is a promising therapeutic target, but there are no inhibitors reported on this specific axis.. A luciferase assay was applied to screen potential inhibitors of Otub1/c-Maf. Annexin V staining/flow cytometry was applied to evaluate cell apoptosis. Immunoprecipitation was applied to examine protein ubiquitination and interaction. Xenograft models in nude mice were used to evaluate anti-myeloma activity of AVT.. Acevaltrate (AVT), isolated from Valeriana glechomifolia, was identified based on a bioactive screen against the Otub1/c-Maf/luciferase system. AVT disrupts the interaction of Otub1/c-Maf thus inhibiting Otub1 activity and leading to c-Maf polyubiquitination and subsequent degradation in proteasomes. Consistently, AVT inhibits c-Maf transcriptional activity and downregulates the expression of its target genes key for myeloma growth and survival. Moreover, AVT displays potent anti-myeloma activity by triggering myeloma cell apoptosis in vitro and impairing myeloma xenograft growth in vivo but presents no marked toxicity.. The natural product AVT inhibits the Otub1/c-Maf axis and displays potent anti-myeloma activity. Given its great safety and efficacy, AVT could be further developed for MM treatment. Video Abstract.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Survival; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Female; Humans; Iridoids; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Proto-Oncogene Proteins c-maf

Valepotriates are iridoids found in variable amounts in Valerianaceae and might be among the bioactive compounds which confer anxiolytic properties to the Valeriana species. On the other hand, unspecific cytotoxicity has also been described. Presently, however, no particular molecular target has been defined for these compounds. Here we studied the effect of valtrate, acevaltrate, and 1- β-acevaltrate isolated from Valeriana glechomifolia on the enzymatic activity of rat P-type ATPases. Valepotriates did not affect rat skeletal muscle sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) activity at the highest concentration used (100 µM). In contrast, the same concentration inhibited roughly half of the total H⁺/K⁺-ATPase activity from rat gastric epithelium (valtrate 54.6 ± 3.2 %, acevaltrate 60.7 ± 7.3 %, 1- β-acevaltrate 50.2 ± 3.1 %; mean ± SEM, n = 3-5). Finally, these substances showed the highest inhibitory potency toward Na⁺/K⁺-ATPase, and the inhibition curves obtained provided a similar IC₅₀ (in µM) for rat kidney α1 isoform (valtrate 21.2, acevaltrate 22.8, 1- β-acevaltrate 24.4) and brain hemispheres α2/ α3 isoforms (valtrate 19.4, acevaltrate 42.3, 1- β-acevaltrate 38.3). Our results suggest that P-type ATPases are differentially inhibited by valepotriates and that Na⁺/K⁺-ATPase might be one of their molecular targets in vivo.

Topics: Adenosine Triphosphatases; Animals; Brain; Epithelium; H(+)-K(+)-Exchanging ATPase; Inhibitory Concentration 50; Iridoids; Kidney; Male; Rats; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Potassium-Exchanging ATPase; Stomach; Valerian

To provide scientific basis for the utilization and development of Valeriana jatamansi by setting up the quality control specification of V. jatamansi.. The pharmacognostical methods were applied. The extract of V. jatamansi was examined. Moisture and ash were determined. And the bioactive constituents were analyzed by TLC and HPLC.. The morphological and histological characters of V. jatamansi were observed. Content of total ash, acid-insoluble ash, and moisture of 15 samples from different habitats and times were determined. The qualitative and quantitative analysis of valtrate and acevaltrate by TLC and HPLC were preformed respectively.. The established method can be used for the quality control of V. jatamans.

Topics: Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Iridoids; Pharmacognosy; Plant Roots; Plants, Medicinal; Quality Control; Rhizome; Valerian

Valeriana glechomifolia is a plant species endemic to southern Brazil that accumulates valepotriates, which are terpene derivatives, in all of its organs. Valepotriates are the presumed sedative generic components of the pharmaceutically used species of Valeriana. The influence of various concentrations of the auxins indole-3-acetic acid, indole-3-butyric acid and alpha-naphthaleneacetic acid on the growth of micropropagated V. glechomifolia was investigated under conditions of transient and continuous exposure. Changes in the development of roots and shoots as well as the production of the valepotriates acevaltrate, valtrate and didrovaltrate (analyzed by high-performance liquid chromatography) were evaluated. The best performance in valepotriate production, growth and survival under ex vitro conditions following plant acclimatization was achieved in the continuous presence of 5.71 microM IAA. When cultured in medium containing IAA plants produced stable levels of valepotriates throughout the entire cultivation period.

Topics: Acclimatization; Indoleacetic Acids; Indoles; Iridoids; Naphthaleneacetic Acids; Plant Roots; Plant Shoots; Valerian

To compare the contents of three valepotrates intraspecifically and intraspecifically in three medicinal Valeriana plants grown in different areas in China.. The method of RE-HPLC was adopted.. The results showed that the contents of three valepotriates in Valeriana jatamansi Jones, V. officinalis L. and V. officinalis var. latifolia Miq. were different. Among them, that of Valeriana jatamansi Jones was the highest. The contents of three valepotrates in Valeriana jatamansi Jones varied significantly from different areas, samples collected from Longli of Guizhou province ranking the highest. The contents of three valepotriates in V. officnalis L. also varied significantly from different areas, samples from Liuba of Shaanxi province showing the highest. The results also showed that the contents of three valepotriates in underground part are all higher than that in aerial part.. The interspecific and intraspecific differences of valepotriates in three Valeriana plans were obvious.

Topics: Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Iridoids; Pharmacognosy; Plants, Medicinal; Species Specificity; Valerian

Valtrate, DIA-valtrate, acevaltrate, 1-beta-acevaltrate and didrovaltrate have been quantitatively estimated by reversed-phase HPLC in the leaves, flowers, stems and roots of Valeriana glechomifolia Meyer, V. catharinensis Graebn., V. chamaedryfolia Cham. & Schltdl., V. eichleriana (C.A.Mull.) Graebn., V. polysthachya Smith, V. scandens L., V. eupatoria Sobral, V. salicariifolia Vahl and V. tajuvensis Sobral. All plants presented valepotriates being V. glechomifolia the richest one, followed by V. eupatoria, V. eichleriana and V. tajuvensis.

Topics: Brazil; Chromatography, High Pressure Liquid; Iridoids; Plant Extracts; Plant Leaves; Plant Roots; Plant Stems; Pyrans; Valerian

The effect of a mixture of valepotriates on the elevated plus-maze performance of diazepam withdrawn rats was evaluated. The rats were chronically (28 days) treated with diazepam (doses increased up to 5.0 mg/kg) and then treated with control solution for 3 days to induce a withdrawal syndrome. Chronically vehicle-treated rats were used as control. The abstinent animals treated with vehicle showed a significant decrease in the percentage of time spent in the open arms when compared with the control animals. Diazepam and valerian 12.0 mg/kg reversed this anxiogenic effect. Valerian 6.0 mg/kg did not show any difference in relation to the others group.

Topics: Analysis of Variance; Animals; Behavior, Animal; Diazepam; Injections, Intraperitoneal; Iridoids; Male; Physical Conditioning, Animal; Plant Extracts; Plants, Medicinal; Psychotropic Drugs; Pyrans; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Valerian