Allelopathic studies with furanocoumarins isolated from Ducrosia anethifolia. In vitro and in silico investigations to protect legumes, rice and grain crops.

Six different furanocoumarins were isolated from the aerial parts of Ducrosia anethifolia and tested in vitro for plant cell elongation in etiolated wheat coleoptile. They were also tested for their ability to control three different weeds: ribwort plantain, annual ryegrass, and common purslane. These compounds exhibited strong inhibition of plant cell elongation. In the case of (+)-heraclenin, the IC50 was lower than 20 µM, indicating a better inhibition than the positive control Logran®. Computational experiments for docking and molecular dynamics revealed for the investigated furanocoumarins bearing an epoxide moiety an improved fitting and stronger interaction with the auxin-like TIR1 ubiquitin ligase. Furthermore, the formed inhibition complex remained also stable during dynamic evaluation. Bidental interaction at the active site, along with an extended hydrogen-bond lifetime, explained the enhanced activity of the epoxides. The in vitro weed bioassay results showed that Plantago lanceolata was the most affected weed for germination, root, and shoot development. In addition, (+)-heraclenin displayed better inhibition values than positive control even at 300 µM concentration.

Safety and risks of CBD oils purchased online: unveiling uncertain quality and vague health claims.

Introduction: The unmet need for highly effective, naturally derived products with minimal side effects results in the over-popularity of ever-newer medicinal plants. In the middle of 2010, products containing cannabidiol (CBD), one of the special metabolites of Cannabis sativa, started to gain popularity. For consumers and healthcare providers alike, the legal context surrounding the marketing of CBD products is not entirely clear, and the safety of using some products is in doubt. Companies in the online medicinal product market profit from the confusion around CBD oils. Methods: In our study, we employed a complex method known as risk-based safety mapping of the online pharmaceutical market, which included health claim content analysis of online stores, test purchases, and labeling and quantitative analysis of the CBD content. Results: There were discovered 16 online retailers selling an average of 2-7 goods and CBD oils with a concentration of 3%-5% (30-50 mg/mL) CBD. The majority (n/N = 10/16, 62.5%) displayed potential health-related benefits indirectly on their website, and in the case of one web shop (n/N = 1/16, 6.3%), we detected COVID-19-related use. Altogether, 30 types of purported "indications" were collected. A total of 12 CBD oil products were test-purchased from online retailers in December 2020. Upon evaluating the packaging and product information, we noticed that three products (n/N = 3/12, 25%) lacked instructions on use, hence increasing the risk of inappropriate application and dosing. The cannabidiol content was quantified using UHPLC. The measured CBD concentrations of the products ranged from 19.58 mg/mL to 54.09 mg/mL (mean 35.51 mg/mL, median 30.63 mg/mL, and SD ± 12.57 mg/mL). One (8.33%) product was underlabeled, five (41.67%) were over-labeled, and only every second product (50%) was appropriately labeled based on the quantitative assessment of CBD concentration. Discussion: Further research and quality control are necessary to establish the regulatory context of the usage and classification of CBD and other cannabinoids in nonmedicinal products (e.g., food supplements), as authorities and policymakers worldwide struggle with the uncertainties surrounding CBD products.

Antiproliferative and cytotoxic effects of sesquiterpene lactones isolated from Ambrosia artemisiifolia on human adenocarcinoma and normal cell lines.

CONTEXT: Ambrosia artemisiifolia L. (Asteraceae) contains sesquiterpene lactones as characteristic secondary metabolites. Many of these compounds exert antiproliferative and cytotoxic effects. OBJECTIVE: To isolate the sesquiterpene lactones from the aerial part of A. artemisiifolia and to elucidate their cytotoxic, antiproliferative and antibacterial effects. MATERIALS AND METHODS: The compounds were identified by one-dimensional (1D) and 2D NMR, HR-MS spectroscopy from the methanol extract. Isolated compounds were investigated for their cytotoxic and antiproliferative effects on human colonic adenocarcinoma cell lines and human embryonal lung fibroblast cell line using MTT assay. The selectivity of the sesquiterpenes was calculated towards the normal cell line. To check the effect of drug interactions between compounds and doxorubicin, multidrug-resistant Colo 320 cells were used. RESULTS: A new seco-psilostachyinolide derivative, 1,10-dihydro-1'-noraltamisin, and seven known compounds were isolated from the methanol extract. Acetoxydihydrodamsin had the most potent cytotoxic effect on sensitive (Colo205) cell line (IC50 = 7.64 µM), also the strongest antiproliferative effect on Colo205 (IC50 = 5.14 µM) and Colo320 (IC50 = 3.67 µM) cell lines. 1'-Noraltamisin (IC50 = 8.78 µM) and psilostachyin (IC50 = 5.29 µM) showed significant antiproliferative effects on the multidrug-resistant Colo320 cell line and had moderate selectivity against human embryonal lung fibroblast cell line. Psilostachyin C exhibited cytotoxic effects on Colo205 cells (IC50 = 26.60 µM). None of the isolated compounds inhibited ABCB1 efflux pump (EP; P-glycoprotein) or the bacterial EPs. DISCUSSION AND CONCLUSIONS: Acetoxydihydrodamsin, 1'-noraltamisin, and psilostachyin showed the most remarkable cytotoxic and antiproliferative activity on tumour cell lines and exerted selectivity towards MRC-5 cell line.

Stellaria media tea protects against diabetes-induced cardiac dysfunction in rats without affecting glucose tolerance.

Background and aim: Common chickweed (Stellaria media) tea has traditionally been applied for treatment of various metabolic diseases including diabetes in folk medicine; however, experimental evidence to support this practice is lacking. Therefore, we aimed to assess the effect of Stellaria media tea on glucose homeostasis and cardiac performance in a rat model of diabetes. Experimental procedure: Hot water extract of Stellaria media herb were analyzed and used in this study, where diabetes was induced by fructose-enriched diet supplemented with a single injection of streptozotocin. Half of the animals received Stellaria media tea (100 mg/kg) by oral gavage. At the end of the 20-week experimental period, blood samples were collected and isolated working heart perfusions were performed. Results and conclusion: Compared to the animals receiving standard chow, serum fasting glucose level was increased and glucose tolerance was diminished in diabetic rats. Stellaria media tea did not affect significantly fasting hyperglycemia and glucose intolerance; however, it attenuated diabetes-induced deterioration of cardiac output and cardiac work. Analysis of the chemical composition of Stellaria media tea suggested the presence of rutin and various apigenin glycosides which have been reported to alleviate diabetic cardiomyopathy. Moreover, Stellaria media prevented diabetes-induced increase in cardiac STAT3 phosphorylation. We demonstrated for the first time that Stellaria media tea may beneficially affect cardiac dysfunction induced by diabetes without improvement of glucose homeostasis. Rutin and/or apigenin glycosides as well as modulation of STAT3 signaling may be implicated in the protection of Stellaria media tea against diabetic cardiomyopathy.

Ducrosia spp., Rare Plants with Promising Phytochemical and Pharmacological Characteristics: An Updated Review.

The rare genus Ducrosia (Apiaceae family) consists of six species, which are mainly native to Asia, specifically to Iran and Iraq. The aerial parts of D. anethifolia, as the most common species, have been traditionally consumed to relieve headache, backache and colic pain, and have also been used as an anxiolytic, an antidepressant, and for treating insomnia. The antispasmodic and carminative effects of D. assadii, and the analgesic activity of D. flabellifolia, along with the insecticidal activities and use as a remedy of skin infections of D. ismaelis, have been previously documented. Among the 49 non-volatile secondary metabolites identified from D. anethifolia and D. ismaelis, 17 linear furanocoumarins and 8 flavonoids have been characterized. The essential oil compositions of four species, including D. anethifolia, D. assadii, D. flabellifolia and D. ismaelis, have been analyzed, whereby aldehyde hydrocarbons, including decanal (10.1‒74.0%) and dodecanal (7.2‒33.41%), and α-pinene (4.0‒70.3%), were identified as the main aroma constituents. From the species of the genus, the bioactivities of D. anethifolia, as well as D. ismaelis, D. assadii and D. flabellifolia, have been previously investigated. Except one clinical trial, all the pharmacological data are derived from preclinical tests, predominantly focusing on antimicrobial, antioxidant, antiproliferative and cytotoxic activities in vitro, and neuroprotective, antidiabetic and analgesic effects in vivo. Considering the vast ethnobotanical uses of the plants in Iranian folk medicine, the phytochemical and pharmacological analysis of un-investigated species might be promising. Furthermore, due to extensive consumption of the Ducrosia genus, more scientific data are needed to support the safety and efficacy of these plants.

Comprehensive chemotaxonomic analysis of saffron crocus tepal and stamen samples, as raw materials with potential antidepressant activity.

Saffron crocus (Crocus sativus L.) has been widely grown in Iran. Its stigma is considered as the most valuable spice for which several pharmacological activities have been reported in preclinical and clinical studies, the antidepressant effect being the most thoroughly studied and confirmed. This plant part contains several characteristic secondary metabolites, including the carotenoids crocetin and crocin, and the monoterpenoid glucoside picrocrocin, and safranal. Since only the stigma is utilized industrially, huge amount of saffron crocus by-product remains unused. Recently, the number of papers dealing with the chemical and pharmacological analysis of saffron is increasing; however, there are no systematic studies on the chemical variability of the major by-products. In the present study, we harvested saffron crocus flowers from 40 different locations of Iran. The tepals and stamens were separated and subjected to qualitative and quantitative analysis by HPLC-DAD. The presence and amount of seven marker compounds, including crocin, crocetin, picrocrocin, safranal, kaempferol-3-O-sophoroside, kaempferol-3-O-glucoside, and quercetin-3-O-sophoroside were determined. The analytical method was validated for filter compatibility, stability, suitability, accuracy, precision, intermediate precision, and repeatability. Tepal and stamen samples contained three flavonol glycosides. The main constituent of the tepals was kaempferol-3-O-sophoroside (62.19-99.48 mg/g). In the stamen, the amount of flavonoids was lower than in the tepal. The amount of kaempferol-3-O-glucoside, as the most abundant compound, ranged between 1.72-7.44 mg/g. Crocin, crocetin, picrocrocin, and safranal were not detected in any of the analysed samples. Our results point out that saffron crocus by-products, particularly tepals might be considered as rich sources of flavonol glucosides. The data presented here can be useful in setting quality standards for plant parts of C. sativus that are currently considered as by-products of saffron production.

Effect of Stellaria media Tea on Lipid Profile in Rats.

BACKGROUND: In folk medicine, common chickweed (Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of Materials and Methods. Adult male Wistar rats were divided into 3 groups. The (i) control group received standard laboratory chow, the (ii) hypercholesterolemic group received cholesterol-enriched diet, and the (iii) chickweed-treated hypercholesterolemic group received cholesterol-enriched diet and 100 mg/kg body weight Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of. RESULTS: Cholesterol-enriched diet significantly increased serum total cholesterol, LDL- and HDL-cholesterol levels, but did not affect triacylglycerol concentrations. The addition of chickweed to the diet did not cause any significant change in serum lipid profile or body weight increase. Liver and kidney functions were unaltered and cardiac morphology and function were not changed due to Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of. CONCLUSION: Although chickweed does not seem to be toxic, our results do not support the rationale of its use in the treatment of hypercholesterolemia.

The Effects of a Fixed Combination of Berberis aristata and Silybum marianum on Dyslipidaemia - A Meta-analysis and Systematic Review.

A fixed combination of Berberis aristata and Silybum marianum (Berberol) has been used by patients with dyslipidaemia. The aim of the present meta-analysis was to systematically evaluate the efficacy and safety of a fixed combination of B. aristata and S. marianum (Berberol) on serum lipid levels compared to placebo in a meta-analysis based on randomised, controlled trials. The meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using the PICO (patients, intervention, comparison, outcome) format, and it was registered in the International Prospective Register of Systematic Reviews. The Cochrane Central Register of Controlled Trials, PubMed, Embase, and Web of Science databases were searched for relevant studies. Placebo-controlled clinical studies involving adult patients with a condition of dyslipidaemia and receiving a fixed combination of B. aristata and S. marianum were included. Four randomised trials, including a total of 491 patients, were pooled in statistical analysis. According to the present meta-analysis, Berberol significantly lowered the low-density lipoprotein level, total cholesterol, fasting plasma glucose levels, and the Homeostatic Model Assessment index compared to placebo; however, its effects on the high-density lipoprotein level, triglyceride level, and body mass index were not statistically significant by the end of a 3-month treatment period. Berberol appeared to be safe, and it did not increase the levels of alanine transaminase, aspartate transaminase, and creatine kinase enzymes. Berberol is an effective and presumably safe complementary therapy for the treatment of dyslipidaemia; however, the evidence supporting its use is very limited. The optimum dose and duration of treatment are unclear. A comprehensive evaluation of efficacy and safety is required in further high-quality clinical studies involving larger patient populations.

Effect of green tea on the gastrointestinal absorption of amoxicillin in rats.

BACKGROUND: The investigation of food-drug and plant-drug interactions has become increasingly important. In case of antibiotics, it is essential to achieve and maintain a plasma concentration sufficient for the antimicrobial action. Although, on theoretical basis, the interaction of polyphenols and antibiotics may be hypothesized, experimental data are lacking to assess its clinical relevance. The aim of our study was to assess the interaction between one of the most widely used antibiotics, amoxicillin, and green tea, the most frequently consumed drink with high polyphenol content. METHODS: The effects of green tea on the plasma level of amoxicillin was studied in an in vivo experiment in rats. The plasma level of amoxicillin was monitored by LC-MS/MS for 240 min after oral administration. The polyphenol content of green tea was determined by the Folin-Ciocalteu method. RESULTS: The peak plasma concentration of amoxicillin significantly decreased upon its co-administration with green tea, although the AUC0-240 of the antibiotic did not decrease significantly in the group treated with amoxicillin suspended in green tea. CONCLUSIONS: Our results suggest a potentially relevant interaction between green tea and amoxicillin, worth being further studied in humans.

Furocoumarin Content of Fennel-Below the Safety Threshold.

Furocoumarins are known for their phototoxic and potential carcinogenic effects. These types of compounds have previously been reported from fennel (Foeniculum vulgare Mill.), a widely used medicinal plant and spice; however, no reliable quantitative data are available on the occurrence of these compounds in fennel fruits. For the first time, we report a comprehensive analysis of fennel fruit samples of different origins, representing a wide range of accessions for their furocoumarin content. Psoralene, 5-methoxypsoralene (bergapten), and imperatorin contents of 33 fennel samples were analyzed using a sensitive liquid chromatography-mass spectrometry (LC-MS) method. When applied at the highest therapeutic dose described in the monograph issued by the European Medicines Agency, the furocoumarin content of the fruits ranged up to 1.22 µg/d, which is below the most restrictive recommendations. Based on our findings, fennel consumption can be considered as safe, at least based on its low furocoumarin content.

The combination of hawthorn extract and camphor significantly increases blood pressure: A meta-analysis and systematic review.

BACKGROUND: A fixed combination of hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen®) has been used in the therapy of hypotension for decades. Although its efficacy was evaluated in clinical trials, these studies have not been critically assessed in meta-analyses. PURPOSE: To systematically evaluate the efficacy of a fix combination of camphor and hawthorn extract (Korodin®) on blood pressure and cognition compared to placebo, in a meta-analysis based on randomized controlled trials (RCTs). STUDY DESIGN: The meta-analysis was carried out following the PRISMA guidelines, using the PICO format, and it was registered in the PROSPERO register. METHODS: The Cochrane Central Register of Controlled Trials, PubMed, Embase, and Web of Science databases were searched for relevant studies. Placebo-controlled clinical studies involving adult patients receiving a fix combination of hawthorn extract and camphor were included. No language or publication year restrictions were applied. RESULTS: Four randomized trials including a total of 221 patients were pooled for statistical analysis. According to the present meta-analysis, the fixed combination of hawthorn and camphor significantly increases systolic and diastolic blood pressure compared to placebo (p-values: 0.017 and 0.049, respectively) and had a beneficial, but not statistically significant effect on the cognitive performance in the connect-the-numbers test (p-value: 0.071). CONCLUSION: Korodin® is an effective and presumably safe complementary therapy for the treatment of hypotension. Its blood pressure increasing effect is confirmed; however, the evidence supporting its use is very limited. The optimum dose and duration of treatment is still unclear. The comprehensive evaluation of efficacy and safety is required in further, high-quality clinical studies, involving larger patient populations and comparable endpoints.

Quality control of Hypericum perforatum L. analytical challenges and recent progress.

OBJECTIVES: The most widely applied qualitative and quantitative analytical methods in the quality control of Hypericum perforatum extracts will be reviewed, including routine analytical tools and most modern approaches. KEY FINDINGS: Biologically active components of H. perforatum are chemically diverse; therefore, different chromatographic and detection methods are required for the comprehensive analysis of St. John's wort extracts. Naphthodianthrones, phloroglucinols and flavonoids are the most widely analysed metabolites of this plant. For routine quality control, detection of major compounds belonging to these groups seems to be sufficient; however, closer characterization requires the detection of minor compounds as well. CONCLUSIONS: TLC and HPTLC are basic methods in the routine analysis, whereas HPLC-DAD is the most widely applied method for quantitative analysis due to its versatility. LC-MS is gaining importance in pharmacokinetic studies due to its sensitivity. Modern approaches, such as DNA barcoding, NIRS and NMR metabolomics, may offer new possibilities for the more detailed characterization of secondary metabolite profile of H. perforatum extracts.

The Efficacy of Saffron in the Treatment of Mild to Moderate Depression: A Meta-analysis.

Herbal products, especially Hypericum perforatum extracts, have been widely used as first-line treatments for mild to moderate depression. Recently, several randomized, controlled clinical trials have been conducted to evaluate the efficacy of another plant, saffron (Crocus sativus), in mild to moderate depression. We have carried out a literature review of currently available published randomized, controlled clinical trials to give an up-to-date evaluation of the efficacy of saffron in mild to moderate depression, compared to placebo or routinely used antidepressants. The meta-analysis is reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines using the PICO (patients, intervention, comparison, outcome) format and was conducted using the statistical programs Comprehensive Meta-analysis and RevMan. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science databases were searched for relevant studies. Only placebo or active controlled, randomized clinical studies involving patients suffering from mild to moderate depression and using pharmacological doses of saffron per os were included. Hedges' g was used to calculate effect sizes. Risk of bias was assessed using the Cochrane Collaboration tool, and heterogeneity was tested by both performing the Cochran's Q test and calculating Higgins' I2 indicator. Eleven randomized trials were included in the qualitative analysis, and nine were pooled for statistical analysis. According to the present meta-analysis, saffron has a significant effect on the severity of depression. Available data from randomized, controlled clinical trials support that saffron is significantly more effective than placebo (g = 0.891; 95% CI: 0.369 - 1.412, p = 0.001), and non-inferior to tested antidepressant drugs (g = - 0.246; 95% CI: - 0.495 - 0.004, p = 0.053).

In vivo screening of diterpene alkaloids using bdelloid rotifer assays.

The group of diterpene alkaloids contains numerous compounds with complex chemistry and diverse pharmacological activities. Beside toxicity, these compounds possess activity on the cardiovascular system, tumor cell lines and nervous system. The pharmacological properties have been described using in vitro and in vivo techniques; however, the bioactivities of many compounds have not thoroughly been studied. Here we report on the in vivo evaluation of ten diterpene alkaloids using bdelloid rotifer assays. Napelline exerted toxic effects on rotifers, while wide tolerance range was observed for other investigated compounds. Weak toxicity of songorine is supported by our experiment. Toxicological data for senbusine A, senbusine C, septentrioidine and hetisinone are reported for the first time.

Diterpene Lipo-Alkaloids with Selective Activities on Cardiac K+ Channels.

Aconitum diterpene alkaloids are known for their remarkable toxicity, which is due to their effect on ion channels. Activation of voltage-gated Na+ channels is the major cause of their cardiotoxicity, however, influence on K+ channels may also play a role in the overall effect.Here we report the synthesis of a series of lipo-alkaloids, including four new compounds, based on the 14-benzoylaconine structure, which is the core of a vast number of diterpene alkaloids naturally occurring in Aconitum species. The activities of these compounds were measured in vitro on K+ ion channels using the whole-cell patch-clamp technique. Structure-activity analysis was carried out based on the data of 51 compounds (32 genuine diterpene alkaloids, 5 fatty acids, and 14 lipo-alkaloids). Depending on their substitution, these compounds exert different activities on GIRK (G protein-coupled inwardly-rectifying potassium channel) and hERG (human ether-à-go-go-related gene) channels. Fatty acids and diterpene alkaloids show lower activity on the GIRK channel than lipo-alkaloids. Lipo-alkaloids also have less pronounced hERG inhibitory activity compared to the cardiotoxic aconitine. Considering the GIRK/hERG selectivity as an indicator of perspective therapeutic applicability, lipo-alkaloids are significantly more selective than the genuine diterpene alkaloids. 14-Benzoyl-8-O-eicosa-8Z,11Z,14Z-trienoate and 14-benzoyl-8-O-eicosa-11Z,14Z,17Z-trienoate are strong and selective inhibitors of GIRK channels, thus, they are promising subjects for further studies to develop diterpene alkaloid-based antiarrhythmic pharmacons.

Repeated-dose toxicity of common ragweed on rats.

Ambrosia artemisiifolia L. is an invasive species with highly allergenic pollens. Ragweed originates from North America, but it also occurs and is spreading in Europe, causing seasonal allergic rhinitis for millions of people. Recently, the herb of A. artemisiifolia has gained popularity as medicinal plant and food. The effects of its long-term intake are unknown; there are no toxicological data to support the safe use of this plant. The aim of our study was to assess the repeated dose toxicity of A. artemisiifolia on animals. Ragweed puree was administered in low dose (500 mg/kg b. w.) and high dose (1000 mg/kg b. w.) to male Wistar rats according to 407 OECD Guidelines for the Testing of Chemicals. Clinical symptoms, various blood chemical parameters, body weight and organ weights of the rats were measured. Reduced liver function enzymes (AST, ALT), reduced triglyceride level in the low dose and increased carbamide level in the high dose group were observed. The weight of the liver relative to body weight was significantly reduced in both groups, while the brain weight relative to body weight was significantly elevated in both groups. According to our results, the repeated use of ragweed resulted in toxic effects in rats and these results question the safety of long-term human consumption of common ragweed.

Identification of diterpene alkaloids from Aconitum napellus subsp. firmum and GIRK channel activities of some Aconitum alkaloids.

Diterpene alkaloids neoline (1), napelline (2), isotalatizidine (3), karakoline (4), senbusine A (5), senbusine C (6), aconitine (7) and taurenine (8) were identified from Aconitum napellus L. subsp. firmum, four (2-4, 6) of which are reported for the first time from this plant. The structures were determined by means of LC-MS, 1D and 2D NMR spectroscopy, including (1)H-(1)H COSY, NOESY, HSQC and HMBC experiments. Electrophysiological effects of the isolated compounds, together with nine diterpene alkaloids previously obtained from Aconitum toxicum and Consolida orientalis were investigated on stable transfected HEK-hERG (Kv11.1) and HEK-GIRK1/4 (Kir3.1 and Kir3.4) cell lines using automated patch clamp equipment. Significant blocking activity on GIRK channel was exerted by aconitine (7) (45% at 10 µM), but no blocking activities of the other investigated compounds were detected. The tested compounds were inactive on hERG channel in the tested concentration. The comparison of the previously reported metabolites of A. napellus subsp. firmum and compounds identified in our experiment reveals substantial variability of the alkaloid profile of this taxon.