iridoids and valtrate

Serious sleep problems are common in children with an intellectual deficit (ID), and are often the source of much distress for both the child and caregivers. As yet, no satisfactory long-term treatment exists for intransigent sleep difficulties in children with an ID. Valerian, Valeriana spp., has been used for thousands of years to induce relaxation and sleep. Scientific investigation of valerian's sleep promoting ability in humans, whilst limited, has yielded promising findings. This initial study aimed to explore valerian's potential for assisting in the treatment of sleep problems in children with an ID. Five children with varying intellectual deficits and different primary sleep problems underwent eight continuous weeks of monitoring via sleep diaries, adhering to a double blind, placebo controlled and randomised design. Compared to baseline and placebo, valerian treatment led to significant reductions in sleep latencies and nocturnal time awake, lengthened total sleep time and improved sleep quality. The treatment was apparently most effective in children with deficits that involved hyperactivity. Although the findings are preliminary and in need of replication, there is evidence to suggest that valerian may be useful in the safe and effective long-term treatment of intransigent sleep difficulties in children with ID's, and therefore warrants further investigation.

Topics: Administration, Oral; Adolescent; Attention Deficit and Disruptive Behavior Disorders; Child; Cross-Over Studies; Double-Blind Method; Female; Humans; Intellectual Disability; Iridoids; Male; Phytotherapy; Plant Extracts; Plant Roots; Sleep Wake Disorders; Surveys and Questionnaires; Treatment Outcome; Valerian

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

Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated.. GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect.. Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls.. Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Glioblastoma; Humans; Iridoids; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Signal Transduction; Valerian

Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear.. To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms.. Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1.. Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest.

Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin B1; Female; Humans; Iridoids; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Pancreatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Reactive Oxygen Species; Signal Transduction; STAT3 Transcription Factor; Valerian; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Caspase 8; Cell Cycle Checkpoints; Cell Movement; Epithelial Cells; Humans; Iridoids; MCF-7 Cells; Valerian

Three new minor valepotriate isomers, jatamanvaltrates Z1 (1), Z2 (2), and Z3 (3), have been isolated from the whole plants of Valeriana jatamansi (syn. Valeriana wallichii.). Their structures were elucidated by extensive spectroscopic analysis, especially 2D NMR and ESI-MS/MS

Topics: Antineoplastic Agents, Phytogenic; Colonic Neoplasms; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Humans; Inhibitory Concentration 50; Iridoids; Isomerism; Male; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Roots; Prostatic Neoplasms; Valerian

A simple and selective liquid chromatography-tandem mass spectrometric method for determination of valtrate in rat plasma was developed in this study. Chromatographic separation was achieved on a Thermo BDS HYPERSIL C18 column using acetonitrile-water-formic acid (75 : 25 : 0.1, v/v/v) as mobile phase in an isocratic mode of elution at a flow rate of 300 µL/min. MS-MS detection was performed in a positive ion electrospray ionization mode with the ion transitions 445.2 → 219.2 for valtrate and 355.2 → 135.1 for internal standard (sesamin). The developed method exhibited a linear dynamic range over 5.65-1695 ng/mL for valtrate in rat plasma. The overall extraction recovery of valtrate from plasma was 86.13-88.32%. The intra- and inter-day accuracy and precision were within the pre-defined limits of ≤15% at all concentrations. The method was successfully applied to pharmacokinetic studies of valtrate in rats.

Topics: Animals; Chromatography, Liquid; Iridoids; Linear Models; Male; Rats; Rats, Wistar; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

Identification of novel chemotherapeutic agents from traditional medicines and elucidation of the molecular basis of their anticancer effects are critical and urgently needed for modern pharmacotherapy. We previously found that analogs of the compounds present in Valeriana jatamansi, a traditional medicine used to treat mental disorders, possess notable antitumor properties; however, the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the anticancer effects of IVHD-valtrate, one of the most active Valeriana jatamansi derivatives, against human ovarian cancer cells in vitro and in vivo. IVHD-valtrate inhibited the growth and proliferation of the A2780 and OVCAR-3 ovarian cancer cell lines in a concentration-dependent manner, while relatively low cytotoxicity to immortalized non-tumorigenic human ovarian surface epithelial cells (IOSE-144) was observed. Treatment with IVHD-valtrate arrested the ovarian cancer cells in the G2/M phase and induced apoptosis, and significantly suppressed the growth of A2780 and OVCAR3 xenograft tumors in a dose-dependent manner. The detailed in vitro and in vivo study on the molecular mechanisms of this compound demonstrated that IVHD-valtrate exposure modulated the expression of numerous molecules involved in cell cycle progression and apoptosis regardless of p53 status, leading to increase the level of p53, Rb, p21, p27 and decrease Mdm2, E2F1, Cyclin B1, Cdc25C and Cdc2. It also down-regulated Bcl-2/Bax and Bcl-2/Bad ratio and enhanced the cleavage of PARP and Caspases. Our preclinical results indicated IVHD-valtrate is a potential therapeutic agent for ovarian cancer, providing a basis for development of the compound as a novel chemotherapeutic agent.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Cycle; Cell Proliferation; Female; Gene Expression Profiling; Humans; In Vitro Techniques; Iridoids; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Phytotherapy; Plant Extracts; Valerian

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

Rational design by the MO calculation disclosed 5,6-dihydrovaltrate (2) as the bioisostere of valtrate (1), the Rev-export inhibitor with anti-HIV activity. The synthesis of 2 was accomplished by ingenious use of asymmetric Diels-Alder reaction and stereoselective epoxidation associated with the adjacent hydroxyl group. Because of similar biological potency to 1, the analog 2 should be recognized as a promising scaffold for new anti-HIV agents with an unprecedented mechanism of action, inhibition for nuclear export of Rev protein, in the conventional remedy.

Topics: Active Transport, Cell Nucleus; Anti-HIV Agents; Gene Products, rev; HeLa Cells; HIV Infections; Humans; Iridoids; Molecular Conformation

Four new diene valepotriates, sorbifolivaltrates A-D ( 1- 4), and the known compounds isovaltrate ( 5), valtrate ( 6), seneciovaltrate ( 7), valtrate hydrine B3 ( 8), and valtrate hydrine B7 ( 9), have been isolated by bioassay-guided fractionation of the cytotoxic hexanes and methyl ethyl ketone crude extracts of the aerial parts of Valeriana sorbifolia occurring in the Sonoran desert. The structures of 1- 4 were determined on the basis of their high-resolution mass spectrometric and NMR spectroscopic data. All compounds exhibited weak to moderate cytotoxicity against the human metastatic prostate cancer cell line, PC-3M.

Topics: Antineoplastic Agents, Phytogenic; Arizona; Drug Screening Assays, Antitumor; Humans; Iridoids; Male; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plants, Medicinal; 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

Bioassay-guided separation by use of the fission yeast expressing NES of Rev, a HIV-1 viral regulatory protein, resulted in isolation of valtrate (1) as a new Rev-transport inhibitor from the nucleus to cytoplasm from Valerianae Radix. Valtrate (1) also inhibited the p-24 production of HIV-1 virus without showing any cytotoxicity against the host MT-4 cells.

Topics: Biotin; Cell Line; Electrophoresis, Polyacrylamide Gel; Fatty Acids, Unsaturated; HIV Core Protein p24; HIV Reverse Transcriptase; Humans; Iridoids; Reverse Transcriptase Inhibitors; Saccharomyces cerevisiae; Valerian

Valepotriate content levels in samples of in vitro cultures of Valeriana edulis ssp. procera were compared with those of roots and rhizomes of wild plants in the reproductive stage. Rhizomes and roots of regenerated and wild plants showed a similar valepotriate content. The data obtained support the hypothesis that valepotriate production in V. edulis spp. procera is closely related to rhizome and root differentiation. The large-scale propagation of this endangered plant may offer an attractive alternative for its production for medicinal purposes.

Topics: Chromatography, High Pressure Liquid; Iridoids; Mexico; Pentanoic Acids; Plant Leaves; Plant Roots; Plant Shoots; Plants, Medicinal; Pyrans; Regeneration; Rhizome; 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

Valeriana officinalis L. (Valerianaceae) is widely known to be associated with sedative properties. The effects of a valepotriates mixtures on mothers and progeny were evaluated in rats. A 30-day administration of valepotriates did not change the average length of estral cycle, nor the number of estrous phases during this period. Also, there were no changes on the fertility index. Fetotoxicity and external examination studies did not show differences, although internal examination revealed an increase in number of retarded ossification after the highest doses employed--12 and 24 mg/kg. No changes were detected in the development of the offspring after treatment during pregnancy. As for temperature, valepotriates caused a hypothermizant effect after administration by the intraperitoneal route but not after oral administration. Generally, the valepotriates employed induced some alterations after administration by the intraperitoneal route, but doses given orally were innocuous to pregnant rats and their offspring.

Topics: Administration, Oral; Animals; Behavior, Animal; Body Temperature; Embryonic and Fetal Development; Estrus; Female; Fertility; Injections, Intraperitoneal; Iridoids; Maternal-Fetal Exchange; Plant Extracts; Pregnancy; Psychotropic Drugs; Pyrans; Rats; Rats, Wistar

The antagonistic activity of various thiol compounds versus the cytotoxic effects of valtrate and didrovaltrate has been evaluated on cultured hepatoma cells. Compounds with free SH groups like cysteine, mercaptoethanol, dithioerythritol, and glutathione were able to suppress the cytotoxicity of the valepotriates in a dose-dependent way, whereas compounds with blocked SH groups did not antagonize these toxic effects. The possible interactions between the valepotriates and thiol compounds are discussed.

Topics: Animals; Cytotoxins; Iridoids; Liver; Plant Extracts; Pyrans; Rats; Sulfhydryl Compounds; Tumor Cells, Cultured

Topics: Adult; Aged; Autonomic Nervous System Diseases; Family Practice; Female; Humans; Iridoids; Male; Middle Aged; Physician-Patient Relations; Plant Extracts; Psychophysiologic Disorders; Pyrans; Stress, Psychological