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It is estimated that 80% of all synthetic drugs are derived from medicinal plants, and nowadays, many synthetic drugs are derived from medicinal plants. Valeriana officinalis can treat many diseases of the nervous system. A crucial aspect of valerian extract is that it inhibits the proliferation of breast cancer cells. To optimize the yield of bioactive compounds in the V. officinalis root extraction, a response surface methodology-based D-optimal design was used. To fulfill this aim, the effects of various factors such as solvent type and concentration, mixing temperature, ultrasound time, and drying method were examined. The optimal conditions for solvent percentages, mixing temperature, ultrasound time, solvent type, and drying methods were determined to be 94.88%, 25 °C, 48.95 min, methanol, and microwave, respectively, with a desirability of 0.921. The predicted valerenic acid, total phenols, total flavonoids, and antioxidant activity in V. officinalis extract were 1.19 (mg/g DW), 8.22 (mg/g DW), 5.27 (mg/g DW), and 92.64%, respectively. In optimal conditions, the extracted amounts of valerenic acid, total phenols, total flavonoids, and antioxidant activity were 2.07 mg/g DW, 7.96 mg/g DW, 5.52 mg/g DW, and 78.68%, respectively, which were consistent with the model predicted amounts (based on 95% prediction interval). This study could be useful as a model for demonstrating the efficacy of microwave drying to maximize the biochemical content of V. officinalis, as well as the antioxidant activity of the root extracts of V. officinalis on industrial scale. [ABSTRACT FROM AUTHOR]

Plant raw materials with a calming effect on the nervous system are increasingly used in modern phytotherapy. Lavender belongs to this group of plants, due to the content of essential oil with known therapeutic properties and other phytoconstituents that can be responsible for the sedative effect. Our studies confirmed the presence of sesquiterpenic acids characterized by sedative activity in lavender extracts. The contents of valerenic acid and acetoxyvalerenic acids in flowers and leafy stalks of two various Lavandula angustifolia cultivars—'Blue River' and 'Ellagance Purple'—were determined. Analyses of methanolic extracts performed using the HPLC method showed that content of these sesquiterpenic acids varied with the cultivars and the morphological parts of the plant. The amount of acetoxyvalerenic acid was significantly higher than the amount of valerenic acid. In the 'Blue River' cultivar, higher levels of both compounds characterized by sedative properties were found. The content of valerenic acid in flowers ranged from 0.50 mg/100 g d.m. in the 'Ellagance Purple' cultivar to 1.75 mg/100 g d.m. in the 'Blue River' cultivar. In turn, leafy stalks contained 0.81 mg/100 g d.m. of valerenic acid in the 'Ellagance Purple' cultivar and 1.16 mg/100 g d.m. in the 'Blue River' cultivar. Interestingly, the 'Blue River' cultivar contained about 10 times more acetoxyvalerenic acid (65.80 mg/100 g d.m.) in flowers and four times more acetoxyvalerenic acid in leafy stalks (50.1 mg/100 g d.m.), in comparison with the 'Ellagance Purple' cultivar. The higher content of valerenic and acetoxyvalerenic acids in the flowers and leafy stalks of the 'Blue River' lavender cultivar can be important for its possible medical applications. [ABSTRACT FROM AUTHOR]

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines fromSt. John'swort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John's wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin - but not to valerenic acid-is likely to be minimal. [ABSTRACT FROM AUTHOR]

Abstract The present study investigated the effects of valerian methanolic extract and valerenic acid on the expression of LL-37 gene and protein in A549 and MRC5 line cells. After preparing Valerian seeds, sowing them in March 2020, and harvesting the rhizome in October 2020, the extract was prepared from the valerian rhizome by maceration method. Valerian acid content was determined using high performance liquid chromatography (HPLC). Two cell lines (A549 and MRC-5) were used to study the effects of valerian extract, and the MTT test was used to evaluate cell viability. The expression of LL-37 mRNA and protein was assessed by Real-Time PCR and western blot, respectively. In vivo safety assessments and histopathological analysis were also conducted. Data was analyzed by Graphpad Prism 8 software. Valerian methanolic extract and valerenic acid upregulated the LL-37 mRNA and protein expression in both treated cell lines. Valerenic acid showed a greater effect on upregulating LL-37 expression than valerian methanolic extract. A549 cells were more sensitive to valerian methanolic extract compared to MRC5 cells, and its cell viability was reduced. Furthermore, liver and kidney-related safety assessments showed that valerian methanolic extract had no toxic effects. In general, it was concluded that the methanolic extract of valerian as well as the resulting valerenic acid as the most important component of the extract has the ability to upregulate LL-37expression. Therefore, methanolic extract of valerian and valerenic acid can be considered for improving the immune system.

Phytomedicines such as valerian and St. John’s wort are widely used for the treatment of sleeping disorders, anxiety and mild depression. They are perceived as safe alternatives to synthetic drugs, but limited information is available on the intestinal absorption and interaction with human intestinal microbiota of pharmacologically relevant constituents valerenic acid in valerian, and hyperforin and hypericin in St. John’s wort. The intestinal permeability of these compounds and the antidepressant and anxiolytic drugs citalopram and diazepam was investigated in the Caco-2 cell model with bidirectional transport experiments. In addition, interaction of compounds and herbal extracts with intestinal microbiota was evaluated in artificial human gut microbiota. Microbiota-mediated metabolisation of compounds was assessed, and bacterial viability and short-chain fatty acids (SCFA) production were measured in the presence of compounds or herbal extracts. Valerenic acid and hyperforin were highly permeable in Caco-2 cell monolayers. Hypericin showed low-to-moderate permeability. An active transport process was potentially involved in the transfer of valerenic acid. Hyperforin and hypericin were mainly transported through passive transcellular diffusion. All compounds were not metabolized over 24 h in the artificial gut microbiota. Microbial SCFA production and bacterial viability was not substantially impaired nor promoted by exposure to the compounds or herbal extracts.

Plant raw materials with a calming effect on the nervous system are increasingly used in modern phytotherapy. Lavender belongs to this group of plants, due to the content of essential oil with known therapeutic properties and other phytoconstituents that can be responsible for the sedative effect. Our studies confirmed the presence of sesquiterpenic acids characterized by sedative activity in lavender extracts. The contents of valerenic acid and acetoxyvalerenic acids in flowers and leafy stalks of two various Lavandula angustifolia cultivars—‘Blue River’ and ‘Ellagance Purple’—were determined. Analyses of methanolic extracts performed using the HPLC method showed that content of these sesquiterpenic acids varied with the cultivars and the morphological parts of the plant. The amount of acetoxyvalerenic acid was significantly higher than the amount of valerenic acid. In the ‘Blue River’ cultivar, higher levels of both compounds characterized by sedative properties were found. The content of valerenic acid in flowers ranged from 0.50 mg/100 g d.m. in the ‘Ellagance Purple’ cultivar to 1.75 mg/100 g d.m. in the ‘Blue River’ cultivar. In turn, leafy stalks contained 0.81 mg/100 g d.m. of valerenic acid in the ‘Ellagance Purple’ cultivar and 1.16 mg/100 g d.m. in the ‘Blue River’ cultivar. Interestingly, the ‘Blue River’ cultivar contained about 10 times more acetoxyvalerenic acid (65.80 mg/100 g d.m.) in flowers and four times more acetoxyvalerenic acid in leafy stalks (50.1 mg/100 g d.m.), in comparison with the ‘Ellagance Purple’ cultivar. The higher content of valerenic and acetoxyvalerenic acids in the flowers and leafy stalks of the ‘Blue River’ lavender cultivar can be important for its possible medical applications.

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John’s wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John’s wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin – but not to valerenic acid – is likely to be minimal.

Objective: To produce valerenic acid (VA) in Saccharomyces cerevisiae by engineering a heterologous synthetic pathway. Result: Valerena-4,7(11)-diene synthase (VDS) derived from Valeriana officinalis (valerian) was expressed in S. cerevisiae to generate valerena-4,7(11)-diene as the precursor of VA. By overexpressing the key genes of the mevalonate pathway ERG8, ERG12 and ERG19, and integrating 4 copies of MBP (maltose-binding protein)-VDS-ERG20 gene expression caskets into the genome, the production of valerena-4,7(11)-diene was improved to 75 mg/L. On this basis, the cytochrome P450 monooxygenase LsGAO2 derived from Lactuca sativa was expressed to oxidize valerena-4,7(11)-diene to produce VA, and the most effective VA production strain was used for fermentation. The yield of VA reached 2.8 mg/L in the flask and 6.8 mg/L in a 5-L bioreactor fed glucose. Conclusions: An S. cerevisiae strain was constructed and optimized to produce VA, but the valerena-4,7(11)-diene oxidation by LsGAO2 is still the rate-limiting step for VA synthesis that needs to be further optimized in future studies. [ABSTRACT FROM AUTHOR]

In vitro adventitious roots were induced from leaves of Valerianajatamansi to assess their potential as a sustainable alternative to extract pharmaceutically important phytoconstituents. Among the different media used, a significantly (p ≤ 0.05) high root induction (90%) was achieved on Schenk and Hildebrandt (SH) medium fortified with 9.84 µM indole-3-butyric acid (IBA). In addition, various process parameters i.e. IBA concentration, sucrose and medium strength were also optimized under submerged cultivation. The maximum fresh root biomass (144.09 ± 11.36 g/L) with a high relative growth rate (2.01 ± 0.04) and growth index (13.41) was achieved in half-strength SH medium having 2% sucrose and 4.92 µM IBA. Further, a significantly high yield of total valerenic acid derivatives [1525.14 µg/g dry weight (DW)] was recorded in adventitious roots as compared to donor plant parts. Individually, valerenic acid (506.27 µg/g DW) was accumulated higher in plant rhizomes, while acetoxyvalerenic (534.91 µg/g DW) and hydroxyl valerenic acid (919.57 µg/g DW) in adventitious roots. Interestingly, hydroxy valerenic acid was unmeasurable in donor plant parts. The phenolic compounds were also found maximum in adventitious roots (451.85 µg/g DW) with the dominance of pharmaceutically important kaempferol and rutin. A substantial increase in phytochemicals was evident at subsequent culture stages with shortened in vitro cultivation cycle (2 months) than field-grown plants (24 months). Moreover, adventitious roots also accumulated 0.059% essential oil with patchouli alcohol (24%) as a key constituent. Conclusively, an enriched metabolic profile and substantially shorter growth cycle under submerged cultivation undoubtedly demonstrated the potential of induced V. jatamansi adventitious roots as a feasible source of phytoconstituents. Key message: In vitro adventitious roots induced leaf of Valerianajatamansi showed improved metabolic profile and shorter cultivation cycle, thereby exhibiting potential as a sustainable alternative for extraction of industrially important phytoconstituents. [ABSTRACT FROM AUTHOR]

Background: Valerenic acid (VA), a sesquiterpenoid of the plant Valeriana officinalis, has attracted attention of the research community due to its potential positive role against neurodegenerative diseases induced by chemicals. However, the relevant evidence in the literature is scarce. Therefore, this study aimed to examine the putative protective role of VA on the toxic effects of the fungicide benomyl on SH-SY5Y neural cells. Methods: Cell viability was determined via the MTT and NRU assays, DNA damage was assessed via comet assay and apoptosis was evaluated through the expression of relevant genes. Results: According to the results, exposure of the cells to benomyl enhanced viability inhibition and promoted DNA damage and apoptosis since the expression levels of the genes coding for MAPK8, NF-kB, Bax, Caspase-9 and Caspase-3 were increased. Treatment of the cells with VA ameliorated these effects in a concentration dependent manner. Conclusion: It is concluded that the molecular mechanism through which benomyl exerts its toxic action appears to depend on DNA oxidation and apoptosis induction. Furthermore, VA, a plant-derived compound is a protective antioxidant against pesticide-induced toxicity. Therefore, herbs, extracts and compounds of plant origin could be used as nutritional supplements that back up the beneficial role of medicine in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Parkinson´s disease is the most important neuromotor pathology due to the prominent loss of dopaminergic neurons in the substantia nigra pars compacta. There is an inherent deficiency of dopamine in Parkinson´s disease, which is aggravated when neuroinflammatory processes are present. Several biomolecules are interesting candidates for the regulation of inflammation and possible neuroprotection, such as valerenic acid, one of the main components of Valeriana officinalis. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced mouse model of Parkinson's disease was developed to evaluate the motor effects of valerenic acid. The evaluation was carried out with four tests (an invert screen test for muscle strength, cross beam test, open field mobility test and lifting on hind legs test). Subsequently, the neuroinflammatory process was evaluated through ELISA of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and IFN-γ). The decreases in the inflammatory and neurodegenerative processes were evaluated by Western blot and immunohistochemistry analyses of the tissues, which included an evaluation of the tyrosine hydroxylase and GFAP proteins. Finally, the predicted mechanism of action of valerenic acid was supported by molecular docking calculations with the 5-HT5A receptor. The results indicate that the use of valerenic acid as a co-treatment decreases the neuroinflammation in Parkinson's disease induced by MPTP and provides evidence of a decrease in the evaluated pro-inflammatory cytokines and in the amount of GFAP in the mesencephalic area. Valerenic acid prevents neuroinflammation in a Parkinson's disease mouse model, which might reflect the neuroprotection of dopaminergic neurons with the recovery of motor ability.

The quality control of the «Valerian rhizome and roots» herbal substance is carried out using high performance liquid chromatography (HPLC) according to the State Pharmacopoeia of the Russian Federation, XIV edition. The quantitative analysis of the active ingredients in valerian tincture is performed using a non-specific and non-selective spectrophotometric method. Therefore, it is important to introduce in Russia a more modern test procedure for quantitative determination of active ingredients in valerian tincture.The aim of the study was to develop a selective and sensitive HPLC procedure for quantitative determination of the total content of sesquiterpenic acids, expressed as valerenic acid, for the purpose of valerian tincture standardisation.Materials and methods: valerian tincture samples produced by seven Russian manufacturers were used as test samples, and valerenic acid was used as the reference standard. The quantitative analysis of the active ingredients was performed by two methods: spectrophotometry at 512 nm following the reaction of valerenic acid ethylester with hydroxyalamine and ferric chloride, and by HPLC using a Nucleosil C18 column, 125×4.6 mm, 5 µm particle size, in gradient elution mode, with detection at 220 nm.Results: the spectrophotometric technique was shown to be insufficiently specific. The authors of the study validated the chromatographic test procedure, established system suitability criteria, and compared the results obtained by the two test procedures. They also determined a tentative standard of the total content of sesquiterpenic acids, expressed as valerenic acid, obtained by HPLC.Conclusions: the HPLC assay developed for quantitative determination of active ingredients in valerian tincture is more specific as compared to the spectrophotometric technique, as the sum of the peaks of valerenic and acetoxyvalerenic acids and the results for the reference standard are taken into account during calculations. The new test procedure is in line with the cross-cutting standardisation principle and can be recommended for inclusion into the draft monograph «Valerian tincture».

Valeriana jatamansi Jones and Hedychium spicatum Ham-ex-Smith are important medicinal herbs of the Himalayan region, which are highly demanded by pharmaceutical industries. Climatic variability especially increasing temperature and water deficit affects the growth and productivity of these species. In addition, increased temperature and water deficit may trigger the biosynthesis of medicinally important bioactive metabolites, which influence the quality of raw plant material and finished products. Therefore, V. jatamansi and H. spicatum plants were undertaken and subjected to different levels of drought (no irrigation), heat (35 °C), and combined stresses for investigating their physiological and metabolic responses. Both the treatments (individually and in combination) reduced relative water content, photosynthesis, carboxylation efficiency, chlorophyll content, while increased intracellular CO2, malondialdehyde and H2O2 content in both the species. Transpiration and stomatal conductance increased under heat and reduced under drought stress as compared to control. Water use efficiency was found to be increased under drought, while reduced under heat stress. Protein, proline, carotenoid content and antioxidant enzymes activities (superoxide dismutase, peroxidise, catalase) initially increased and thereafter decreased during late stages of stress. Exposure of plants to combined stress was more detrimental than individual stress. In V. jatamansi, exposure to drought stress significantly (p < 0.05) increased valerenic acid content in all plant parts (1.0–6.9 fold) with maximum increase after 20 days of exposure, while under heat stress, valerenic acid content increased (1.0–1.2 fold) in belowground part of V. jatamansi, and decreased (1.1–1.3 fold) in aerial part as compared to control. In H. spicatum, exposure of individual heat stress for 25–30 days and combined stress for 5–15 days significantly (p < 0.05) increased linalool content to 6.2–6.5 fold and 8.3–19.6 fold, respectively, as compared to control. Higher accumulation of bioactive compounds after exposure to mild stress provides encouraging prospects for enhancing pharmaceutical properties of these Himalayan herbs. [ABSTRACT FROM AUTHOR]

Background: Phytochemicals are group of compounds derived from plant resource and shown to have many pharmacological activities. Identification and quantification of chemical constituents in complex matrix of plant is a challenging task. LC-MS is the most prominent analytical technique for this purpose. Purpose: The aim of the present study is identification and quantification of bioactive compounds from Valeriana jatamansi using LC-MS and their in-vitro anti-proliferative screening. Materials and Methods: HPLC-ESI-QTOF-MS/MS separation for qualitative analysis was performed with the aid of an Agilent Poroshell 120 ECC18 column (2.7 μm, 50 mm × 4.6 mm). For quantitative analysis UPLC-ESI-QqQLIT−MS/MS separation was achieved on ACQUITY UPLC BEH™ C18 column (1.7 μm, 50 mm × 2.1 mm). The eluents were water with 0.1% formic acid (A) and acetonitrile (B). The anti-proliferative activity of samples of V. jatamansi on exponentially growing breast cancer cells was determined by the sulphorhodamine B (SRB) assay. Results: An efficient and sensitive LC-MS method was developed for metabolite profiling of five samples of V. jatamansi which resulted in the identification of forty-seven compounds by HPLC-ESI-QTOF-MS/MS. Nine bioactive compounds were quantified for the first time in leaves and roots of V. jatamansi using UPLC-ESI-QqQLIT−MS/MS. Quantitation method was also validated according to ICH guidelines. The correlation coefficient values (r2> 0.9873), LODs and LOQs for each analyte were < 15.7 and 47.6 ng/mL. The intra and inter-day precision variations (RSD) are

Valeriana jatamansi Jones, an important medicinal herb of the Himalayan region, is an essential source of many therapeutic compounds and is traded/consumed in very high volume. The hypothesis of this study was that different seasons and light conditions may affect the content of medicinally valuable components with changes in the morpho-physiological attributes of the plant. Growing plants under suitable light conditions and harvesting of appropriate plant parts in optimum season is crucial for harnessing the full potential of the crop. Thus, the study was carried out to determine the seasonal response of V. jatamansi plants (genetically identical plants of same age) in terms of growth and phytochemical content under two different light conditions (full sunlight and 50% shade). During all seasons, growth parameters (plant height, leaf number, leaf area, relative water content, plant biomass) and the principle bioactive compounds (valerenic acid) were higher under shade conditions, while total flavonoids, tannins, phenolic compounds and antioxidant activities were higher under full sunlight conditions. HPLC analysis revealed that valerenic acid and most of the phenolic content were higher during summer season, especially in leaf part of the plant. The study suggested harvesting of V. jatamansi plants (especially leaf), during summer season to harness high quality raw material and to prevent loss of belowground parts. This strategy can be adopted by farmers for large scale cultivation of species. [ABSTRACT FROM AUTHOR]

The use of new agricultural technologies such as soilless and aeroponic cultivation systems is a valuable approach to medicinal plant production. The present study investigated the prospects of enhancing yield and secondary metabolite production in Valeriana jatamansi under aeroponic cultivation using elicitors, such as yeast extract and methyl jasmonate. Plants were evaluated by measuring growth parameters, photosynthetic rate, and secondary metabolites contents (on a dry weight basis). Maximum plant height (36.83 cm), leaf number (17.67), rootlet number (37.33), and rootlet length (6.90 cm) were observed at 0.5 mg/L yeast extract treatment; whereas treatment levels of 1.5 mg/L yeast extract and 150 µM methyl jasmonate resulted in maximum leaf length (6.95 cm) and leaf width (5.43 cm), respectively. Maximum photosynthetic rate (5.4053 µmol m-2s-1) and stomatal conductance (0.0656 mmol m-2s-1) were recorded at treatment levels of 0.5 mg/L and 1.5 mg/L yeast extract respectively, whereas at 150 µM methyl jasmonate treatment, transpiration rate was 0.9046 mmol m-2s-1. In aeroponic cultivation, the maximum content of valerenic acid and hydroxy valerenic acid was detected in leaf (2.47 and 8.37 mg/g) and root (1.78 and 7.89 mg/g) at treatment levels of 100 µM and 150 µM methyl jasmonate, respectively. Acetoxy valerenic acid was highest in leaf (1.02 mg/g) at 1.5 mg/L yeast extract, and in the root (2.38 mg/g) at 150 µM methyl jasmonate. Gas chromatography-mass spectrometry analysis identified twenty-eight volatile compounds in roots, of which three—isovaleric acid (6.72-50.81%), patchouli alcohol (13.48-25.31%) and baldrinal (0.74-25.26%)—were the major constituents. The results revealed that, besides roots, leaves could also be utilized as a prominent alternative source for targeted secondary metabolites. In conclusion, aeroponic cultivation offers year-round quality biomass production and ease to access subsequent roots harvest in V. jatamansi, to meet the demand of the pharmaceutical industries.

The use of new agricultural technologies such as soilless and aeroponic cultivation systems is a valuable approach to medicinal plant production. The present study investigated the prospects of enhancing yield and secondary metabolite production in Valeriana jatamansi under aeroponic cultivation using elicitors, such as yeast extract and methyl jasmonate. Plants were evaluated by measuring growth parameters, photosynthetic rate, and secondary metabolites contents (on a dry weight basis). Maximum plant height (36.83 cm), leaf number (17.67), rootlet number (37.33), and rootlet length (6.90 cm) were observed at 0.5 mg/L yeast extract treatment; whereas treatment levels of 1.5 mg/L yeast extract and 150 µM methyl jasmonate resulted in maximum leaf length (6.95 cm) and leaf width (5.43 cm), respectively. Maximum photosynthetic rate (5.4053 µmol m-2s-1) and stomatal conductance (0.0656 mmol m-2s-1) were recorded at treatment levels of 0.5 mg/L and 1.5 mg/L yeast extract respectively, whereas at 150 µM methyl jasmonate treatment, transpiration rate was 0.9046 mmol m-2s-1. In aeroponic cultivation, the maximum content of valerenic acid and hydroxy valerenic acid was detected in leaf (2.47 and 8.37 mg/g) and root (1.78 and 7.89 mg/g) at treatment levels of 100 µM and 150 µM methyl jasmonate, respectively. Acetoxy valerenic acid was highest in leaf (1.02 mg/g) at 1.5 mg/L yeast extract, and in the root (2.38 mg/g) at 150 µM methyl jasmonate. Gas chromatography-mass spectrometry analysis identified twenty-eight volatile compounds in roots, of which three—isovaleric acid (6.72-50.81%), patchouli alcohol (13.48-25.31%) and baldrinal (0.74-25.26%)—were the major constituents. The results revealed that, besides roots, leaves could also be utilized as a prominent alternative source for targeted secondary metabolites. In conclusion, aeroponic cultivation offers year-round quality biomass production and ease to access subsequent roots harvest in V. jatamansi , to meet the demand of the pharmaceutical industries. [ABSTRACT FROM AUTHOR]

Free radicals are shown as the main reason of many chronic and degenerative diseases. Because of the toxicity and undesirable effects of synthetic antioxidants, finding of new antioxidant natural agents is very important, especially edible plants. As an edible plant, valerian is used for various aims. Also, Valeriana species are known with their antioxidative compounds. In our previous study, some biological activities of Valeriana alliariifolia Adams roots extracts, collected in 2012, and the chemical compositions of active samples were determined. For this study, after 5 years collected plant materials were investigated again to determine and compare the antioxidant activities, the total phenolic contents and the chemical composition profile of the extracts from different plant-parts and to compare obtained results with the previous data. While RWI, RWM1 and RWM1residue were found most active by DPPH method and AHM1 by FRAP method, REM1 showed the highest activity by CUPRAC method. The high activity of AHM1 is parallel to its phenolic content. It can be thought that the difference between the results of our two studies, is due to the change of plant content from year to year and various environmental factors. This is important for achieving standardization in the production of its preparations. [ABSTRACT FROM AUTHOR]

Adipose tissue is an endocrine organ and its endocrine function is closely associated with type 2 diabetes mellitus. Valeriana officinalis (Valerian) exerts some physiological effects; however, its influence on adipocytes remains unclear. We investigated the effect of methanolic Valerian root extract (Vale) on 3T3-L1 adipocytes. Vale (1, 10, and 100 μg/mL) dose-dependently promoted adipocyte differentiation with increasing lipid accumulation. In addition, Vale significantly increased the mRNA levels in genes associated with adipocyte differentiation, including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α , and adipocyte protein 2, in dose-dependent manner. Vale also significantly enhanced mRNA and protein levels in adiponectin. A PPARγ antagonist assay and a PPARγ binding assay revealed that Vale-induced increased adipocyte differentiation and adiponectin production were partly associated with direct binding to PPARγ. Valerenic acid, a characteristic component in Valerian, also demonstrated the ability to induce adipocyte differentiation and adiponectin secretion, suggesting that it is one of the functional components in Vale. [ABSTRACT FROM AUTHOR]

Extracts from the plant Valeriana officinalis are marketed as an herbal remedy to treat anxiety and insomnia. Valerenic acid (VA) is a major chemical component of Valeriana extracts. To date, there is relatively little information about how VA affects behavior. The purpose of these experiments was to (1) test whether administration of VA induces measurable changes in anxiety-like, depression-like, or locomotor behaviors; (2) determine whether the effects of VA on behavior are dose-dependent; and (3) compare the effects of VA on behavior to those of diazepam, a commonly prescribed treatment for anxiety. Young adult, female mice (C57BL/6J; 3–4 months old; 12 mice/group) were given one of three dosages of VA (3 mg/kg, 6 mg/kg, or 12 mg/kg), diazepam (1 mg/kg), or a vehicle control solution (20% ethanol v/v) by intraperitoneal injection. Thirty minutes after injection, each mouse was tested in the elevated plus maze (EPM), open field test (OFT), and tail suspension test (TST), in that order. All tests were video recorded and analyzed for relevant behavioral parameters. The results demonstrated that VA treatment effectively reduced multiple anxiety-related behaviors measured in the EPM. In fact, at a dose of 12 mg/kg, the anxiolytic effect of VA was just as robust as that of diazepam. Furthermore, the effects of VA on behavior were specifically anxiolytic, as VA did not induce changes in locomotor activity in the OFT, or depression-related behavior as measured in the TST. Our results provide strong support for VA as a putative anxiolytic drug. [ABSTRACT FROM AUTHOR]

The volatile constituents from the n-hexane extracts of the roots and rhizomes of Valeriana officinalis (VO) and Valeriana turkestanica (VT) were investigated by GC-MS analysis. Two VO samples were obtained from cultivation, one from commercially available material, while VT was collected in a mountain of Kazakhstan. The most characteristic components present in all of the analysed samples were sesquiterpenoids. The three investigated samples of VO produced mainly valerenane and kessane sesquiterpenoids. Acetoxyvalerenic acid (33.94%), valerenic acid (15.05%), valerenal (11.93%), valeric acid 2,6-dimethylnon-1-en-3-yn-5-yl ester (5.24%), valerenol (3.31%), elemol (3.19%) and (E)-valerenyl isovalerate (2.53%), were the common components identified in the n-hexane extract from the roots of VT. In comparison to VO this species does not produce kessane sesquiterpenoids and polyunsaturated fatty acids. This study shows that the roots of VT possess compounds of high biological significance, since they have the appropriate contents of valerenic acid and its derivatives, thus VT can be considered as a substitute for VO.

Introduction: Valerenic acid (VA) is a unique and biologically active component in Valeriana officinalis L., which has been reported to have a regulatory effect on the cardiovascular system. However, its therapeutic effects on pathological myocardial hypertrophy (PMH) and the underlying mechanisms are undefined., Objectives: Our study aims to elucidate how VA improves PMH, and preliminarily discuss its mechanism., Methods: The efficacy of VA on PMH was confirmed by in vivo and in vitro experiments and the underlying mechanism was investigated by molecular dynamics (MD) simulations and specific siRNA interference., Results: VA enhanced cardiomyocyte fatty acid oxidation (FAO), inhibited hyper-activated glycolysis, and improved the unbalanced pyruvate-lactate axis. VA could significantly improve impaired mitochondrial function and reduce the triglyceride (TG) in the hypertrophic myocardium while reducing the lactate (LD) content. Molecular mechanistic studies showed that VA up-regulated the expression of peroxisome proliferator-activated receptor-α (PPARα) and downstream FAO-related genes including CD36, CPT1A, EHHADH, and MCAD. VA reduced the expression of ENO1 and PDK4, the key enzymes in glycolysis. Meanwhile, VA improved the pyruvate-lactate axis and promoted the aerobic oxidation of pyruvate by inhibiting LDAH and MCT4. MD simulations confirmed that VA can bind with the F273 site of PPARα, which proposes VA as a potential activator of the PPARα., Conclusion: Our results demonstrated that VA might be a potent activator for the PPARα-mediated pathway. VA directly targets the PPARα and subsequently promotes energy metabolism to attenuate PMH, which can be applied as a potentially effective drug for the treatment of HF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Valerenic acid (VA) is a sesquiterpenoid and a phytoconstituent of the plant valerian used for sleeping disorders and anxiety. The frequency of using herbal components as therapeutic nutritional agents has increased lately. Their ability to improve redox homeostasis makes them a valuable approach against harmful xenobiotics. The purpose of this study was to evaluate the putative beneficial role of VA against the redox-perturbating role of the fungicide benomyl in HepG2 human liver cells in terms of oxidative stress in the cellular environment and in endoplasmic reticulum (ER). Benomyl increased cell total oxidant status and reactive oxygen species production and decreased total antioxidant status. The expression of genes coding for antioxidant molecules, namely, heme oxygenase-1, alpha glutathione s-transferase, NF-ĸB, and liver fatty acid binding protein, were decreased due to benomyl. VA ameliorated these effects. Benomyl also increased ER-stress-related molecules such as endoplasmic reticulum to nucleus signaling 1 protein, glucose-regulated protein 78, and caspase-12 levels, and VA acted also as a preventive agent. These results indicate that VA exerts ameliorative effects after benomyl-induced oxidative stress. VA, a widely used nutritional supplement, is a compound with potent antioxidant properties, which are valuable for the protection of cells against xenobiotic-induced oxidative damage.

Abstract The roots of Valeriana officinalis L. (Valerianaceae) are used for treating sleep disorders and/or mild nerve tension. The effect of valerenic acid on brain-derived neurotrophic factor (BDNF) has not yet been studied, although it is known that gamma-amino butyric acid A (GABA A) receptor is regulated by BDNF, which modulates the depressive-like behavior and neurogenesis. The purpose of this study is to determine the effect of V. officinalis root extract (VO), its main constituents valerenic acid (VA) and acetoxy valerenic acid (AVA) as well as valerenic acid-free (VAF), acetoxy valerenic acid-free (AVAF) extracts and increasing amounts of valerenic acid containing extracts on the BDNF expression in SH-SY5Y cell lines. The effect of methanolic extracts of VO, VA, AVA, VAF, AVAF, and the extracts whose amount of VA were increased gradually, were tested using a Human BDNF ELISA kit with 17 β -estradiol as a positive control. The VO and VA extracts caused a significant (p < 0.001) increase in the BDNF expression in SH-SY5Y cells compared to control. This effect completely disappeared when cells were treated with VAF extract. AVA alone did not show any significant change in the BDNF levels. The extracts with increasing amount of VA led to a concentration- dependent effect on the cells. In conclusion, our findings suggest that the antidepressant-like effect of the VO extract is also related to BDNF expression, and that this is mainly due to the presence of VA in the extract. Removing VA from VO extract leads to a loss of activity. Moreover, the concentration of VA plays a role for BDNF expressions in SH-SY5Y cells, which demonstrates the importance of quality control on the commercially available products. [ABSTRACT FROM AUTHOR]

Phytomedicines such as valerian and St. John's wort are widely used for the treatment of sleeping disorders, anxiety and mild depression. They are perceived as safe alternatives to synthetic drugs, but limited information is available on the intestinal absorption and interaction with human intestinal microbiota of pharmacologically relevant constituents valerenic acid in valerian, and hyperforin and hypericin in St. John's wort. The intestinal permeability of these compounds and the antidepressant and anxiolytic drugs citalopram and diazepam was investigated in the Caco-2 cell model with bidirectional transport experiments. In addition, interaction of compounds and herbal extracts with intestinal microbiota was evaluated in artificial human gut microbiota. Microbiota-mediated metabolisation of compounds was assessed, and bacterial viability and short-chain fatty acids (SCFA) production were measured in the presence of compounds or herbal extracts. Valerenic acid and hyperforin were highly permeable in Caco-2 cell monolayers. Hypericin showed low-to-moderate permeability. An active transport process was potentially involved in the transfer of valerenic acid. Hyperforin and hypericin were mainly transported through passive transcellular diffusion. All compounds were not metabolized over 24 h in the artificial gut microbiota. Microbial SCFA production and bacterial viability was not substantially impaired nor promoted by exposure to the compounds or herbal extracts. • Intestinal permeability was assessed with a validated Caco-2 cell model. • Gut microbiota interactions were investigated with the PolyfermS system. • Valerenic acid, hyperforin, diazepam, and citalopram were highly permeable. • Hypericin was low-to-moderately permeable. • Compounds were not metabolized by the microbiota and did not impact their viability. [ABSTRACT FROM AUTHOR]

Valeriana officinalis is a medicinal herb which produces a suite of compounds in its root tissue useful for treatment of anxiety and insomnia. The sesquiterpene components of the root extract, valerenic acid and valerena-1,10-diene, are thought to contribute to most of the observed anxiolytic of Valerian root preparations. However, valerenic acid and its biosynthetic intermediates are only produced in low quantities in the roots of V. officinalis . Thus, in this report, Escherichia coli was metabolically engineered to produce substantial quantities of valerena-1,10-diene in shake flask fermentations with decane overlay. Expression of the wildtype valerenadiene synthase gene (pZE- wvds ) resulted in production of 12 μg/mL in LB cultures using endogenous FPP metabolism. Expression of a codon-optimized version of the valerenadiene synthase gene (pZE- cvds ) resulted in 3-fold higher titers of valerenadiene (32 μg/mL). Co-expression of pZE- cvds with an engineered methyl erythritol phosphate (MEP) pathway improved valerenadiene titers 65-fold to 2.09 mg/L valerenadiene. Optimization of the fermentation medium to include glycerol supplementation enhanced yields by another 5.5-fold (11.0 mg/L valerenadiene). The highest production of valerenadiene resulted from engineering the codon-optimized valerenadiene synthase gene under strong P trc and P T7 promoters and via co-expression of an exogenous mevalonate (MVA) pathway. These efforts resulted in an E. coli production strain that produced 62.0 mg/L valerenadiene (19.4 mg/L/OD 600 specific productivity). This E. coli production platform will serve as the foundation for the synthesis of novel valerenic acid analogues potentially useful for the treatment of anxiety disorders. [ABSTRACT FROM AUTHOR]

Ferula sumbul (Umbelliferae) roots have a characteristic musk odour and it has been traditionally used for relieving anxiety, as a sedative in hysteria and other nervous disorders. Present investigation aims to develop and validate a simple, robust, accurate and fast analytical ultra-performance liquid chromatography technique for the estimation of valerenic acid in F. sumbul roots. F. sumbul root extract was prepared by refluxing the powdered roots with methanol for 30 minutes. A simple method for the estimation of valerenic acid has been developed and validated using ultra-performance liquid chromatography with photodiode array detector. The estimation was achieved using BEH Shield RP, C-18 column (2.1×50 mm, 1.7 μm) with isocratic elution of methanol and 0.5% phosphoric acid (75:25) at a flow rate of 0.25 ml/min and detection at 218 nm. The method has been developed for the first time and is accurate with good linearity (r2>0.998). F. sumbul roots were found to contain 12.62±0.074 μg/g valerenic acid. The developed method can be selectively used for the estimation of valerenic acid in the roots of F. sumbul. All the validation parameters were found to be within the permissible limits prescribed by ICH guidelines. [ABSTRACT FROM AUTHOR]

The plant natural product, valerenic acid ( 1 ) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as Log P, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library ( 2 – 12 ) was subsequently generated using parallel solution-phase synthesis and Ghosez’s reagent. The chemical structures of all semi-synthetic analogues ( 2 – 12 ) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC 50 values of 2.8–8.3 μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release. [ABSTRACT FROM AUTHOR]

The changes in total phenolics, flavonoids, tannins, valerenic acid, and antioxidant activity were assessed in 25 populations of Valeriana jatamansi sampled from 1200 to 2775 m asl and four habitat types of Uttarakhand, West Himalaya. Significant ( p < 0.05) variations in total phenolics, flavonoids, valerenic acid, and antioxidant activity in aerial and root portions and across the populations were observed. Antioxidant activity measured by three in vitro antioxidant assays, i.e., 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic) (ABTS) radical scavenging, 2,2′-diphenyl-1-picryylhydrazyl (DPPH) free radical scavenging, and ferric-reducing antioxidant power (FRAP) assays, showed significant ( p < 0.05) differences across the populations. However, no clear pattern was found in phytochemicals across the altitudinal range. Among habitat types, (pine, oak, mixed forest, and grassy land), variation in phytochemical content and antioxidant activity were observed. Equal class ranking, neighbor-joining cluster analysis, and principal component analysis (PCA) identified Talwari, Jaberkhet, Manjkhali, and Khirshu populations as promising sources with higher phytochemicals and antioxidant activity. The results recommended that the identified populations with higher value of phytochemicals and antioxidants can be utilized for mass multiplication and breeding program to meet the domestic as well as commercial demand. [ABSTRACT FROM AUTHOR]

Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT 1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT 1B/1D and 5-HT 5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT 5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15 nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15 nmol) or valerenic acid (1 nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT 5A/5B ; 0.01–0.1 nmol); (ii) SB-699551 (selective 5-HT 5A ; up to 10 nmol); (iii) anti-5-HT 5A antibody; (iv) SB-224289 (selective 5-HT 1B ; 0.1–1 nmol); or (v) BRL-15572 (selective 5-HT 1D ; 0.1–1 nmol). Likewise, antinociception by intraplantar ergotamine (15 nmol) and valerenic acid (10 nmol) was: (i) partially blocked by methiothepin (1 nmol), SB-699551 (10 nmol) or SB-224289 (1 nmol); and (ii) abolished by BRL-15572 (1 nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT 5A and 5-HT 1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain. [ABSTRACT FROM AUTHOR]

Valeriana fauriei (V. fauriei), which emits a characteristic and unpleasant odor, is important in traditional medicine. In this study, the expression of terpenoid biosynthetic genes was investigated in different organs that were also screened for volatile compounds including valerenic acid and its derivatives. Specific expression patterns from different parts of V. fauriei were observed using quantitative real-time PCR (qRT-PCR). The highest transcript levels of biosynthetic genes involved in mevalonic acid (MVA) and methylerythritol phosphate (MEP) production were found in the stem. Although the amounts of volatile compounds were varied by organ, most of the volatile terpenoids were accumulated in the root. Gas chromatography mass spectrometry (GC-MS) analysis identified 128 volatile compounds, which represented 65.33% to 95.66% of total volatiles. Certain compounds were only found in specific organs. For example, isovalerenic acid and valerenic acid and its derivatives were restricted to the root. Organs with high transcript levels did not necessarily have high levels of the corresponding chemical constituents. According to these results, we hypothesize that translocation may occur between different organs in V. fauriei. [ABSTRACT FROM AUTHOR]

In a previous study, we demonstrated that a Valeriana officinalis extract could attenuate increases in serum corticosterone levels in a mouse model of physical and psychological stress. In addition, our results showed that the extract could modulate serotonin (5-HT) and norepinephrine (NE) turnover in the hippocampus and amygdala region. In this study, we intended to investigate the effects of valerenic acid (VA), the main component of V. officinalis extract, on corticosterone levels in serum in normal mice and monoamine turnover in hippocampus-amygdala homogenates in a mouse model of physical and psychological stress. To determine the minimum dose of VA for antianxiety effect, eight-week-old ICR mice were orally administered VA (0.2, 0.5, and 1.0 mg/kg/0.3 mL) once daily for 3 weeks to probe for immobility time and serum corticosterone levels. At a VA dose of 0.5 and 1.0 mg/kg, animals showed a decrease in the duration of immobility time and serum corticosterone levels. To confirm the antianxiety effect of VA, eight-week-old ICR mice received VA at a dose of 0.5 mg/kg, orally, once daily for 3 weeks, before being subjected to physical or psychological stress for 3 days, in a specially designed communication box, followed by estimation of levels of monoamines and their metabolites in the hippocampus-amygdala region. In conclusion, VA administration at 0.5 mg/kg can mitigate the physical and psychological stress response by decreasing the turnover of 5-HT to 5-hydroxyindoleacetic acid and NE to 3-methoxy-4-hydroxyphenylethyleneglycol sulfate in the hippocampus and amygdala. [ABSTRACT FROM AUTHOR]

Valeriana jatamansi Jones, commonly known as Indian Valerian or Tagar (Family: Valerinaceae) is used in both traditional and modern systems of medicine. The plants of this species are known for their high content of valerenic acid, the main active constituent of valerian, and high antioxidant activity, and these characteristics have increased the demand for these plants by the pharmaceutical industry. At present, the demand for planting material is largely met from the harvesting of wild plants, which vary in quality and quantity of the active ingredient. Therefore, there is a need to identify individual plants/populations with a higher content of the active ingredients and higher antioxidant activity. We used inter-simple sequence repeats (ISSR) markers in 151 genotypes of 25 V. jatamansi populations to identify markers associated with valerenic acid and antioxidant activity. Of the 130 ISSR primers tested, 20 generated 159 bands, with an average of 7.95 bands per primer. Valerenic acid content was significantly (p < 0.05) higher in the Katarmal (aerial portion 0.57 ± 0.04 %) and Joshimath populations (root portion 1.80 ± 0.12 %). Antioxidant activity using these different in vitro assays varied among the populations and plant portions, with maximum antioxidant activity found in the aerial plant portion (8.63 ± 0.06 mM) and roots [8.36 ± 0.0 mM ascorbic acid equivalents (AAE)/100 g dry weight (dw)] of the Didihat and Katarmal populations, respectively, using the ABTS [2, 2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic)] assay. The DPPH (2, 2-diphenyl-1-picryylhydrazyl free radical scavenging) assay revealed maximum antioxidant activity in the aerial plant portion (15.23 ± 0.09 mM) and roots (17.53 ± 0.04 mM AAE/100 g dw) of the Didihat population. The FRAP (ferric-reducing antioxidant power) assay showed that the roots of plants of the Ukhimath population had significantly higher antioxidant activity (12.71 ± 0.04 mM AAE/100 g dw) than those of other populations of V. jatamansi. Based on the stepwise multiple regression analysis, seven positive and six negative markers showed significant association with valerenic acid content. Antioxidant activity measured by the ABTS, DPPH and FRAP assays showed a positive correlation with 14, 13 and 10 markers, respectively (p < 0.001). These markers have the potential for application in breeding programmes in order to select lineages of V. jatamansi with higher biochemical attributes, especially when no other genetic information, such as linkage maps and quantitative trait loci is available. [ABSTRACT FROM AUTHOR]