Thapsia Garganica Research Articles

Screening of <i>Thapsia garganica</i> for Control of <i>Culex pipiens</i> Mosquito Larvae

In this study, the presence of some secondary metabolites was tested in the aerial parts of the medicinal plant Thapsia garganica L. by screening method, then the effectiveness of its powder using by infusion was examined at different concentrations (15, 30, 45 and 60g/ l) on newly moulted fourth-instar larvae (L4 ) of Culex pipiens L. mosquito. The obtained results revealed that the used plant contains all cited components and exhibits a toxic effect on fourth-instar larvae. This toxicity was evident by an increase in larval mortality with respect to the concentration compared to the control group. The lethal concentrations LC50 and LC90 were estimated at 23.27 g/ l and 69.47 g/ l respectively.

Thapsigargin: a promising natural product with diverse medicinal potential - a review of synthetic approaches and total syntheses.

Thapsigargin, a sesquiterpene lactone, naturally occurring in the roots and fruits of the Mediterranean shrub Thapsia garganica L, is known to the practitioners of traditional medicines since the medieval ages as a cure for rheumatic pain, lung diseases, and female infertility. This naturally occurring guaianolide has shown remarkable activity for Sarco endoplasmic reticulum Ca2+ ATPase inhibition, which eventually renders it fit as a potential candidate for anti-cancer drugs. Mipsagargin, a prodrug derived from thapsigargin, is under clinical trials for the treatment of glioblastoma. Recently, thapsigargin has shown promise as an antiviral against SARS-CoV-2. Limited natural availability and challenging synthesis have prompted research into new synthetic pathways. This review discusses significant synthetic approaches and total syntheses of thapsigargin reported to date.

Chemical Composition and Insecticidal Activity against Tribolium Castaneum of Thapsia garganica L. Seed Essential Oil.

Due to the several side effects of synthetic pesticides, including environmental pollution, threats to human health, and the development of pest resistance to insecticides, the use of alternative healthy, available and efficient agents in pest management strategies is necessary. Recently, the use of essential oil obtained from aromatic plants has shown significant potential for insect pest management. For this reason, the essential oil isolated from seeds of Thapsia garganica L. was investigated for the first time for its chemical profile, and its toxicity and repellency effects against Tribolium castaneum adults. Qualitative and quantitative analyses of the chemical composition by gas chromatography coupled to mass spectrometry (GC/MS) revealed the presence of 18 organic volatiles representing 96.8 % of the total constituents. The main compounds were 1,4-dimethylazulene (51.3 %) followed by methyl palmitate (8.2 %), methyl linoleate (6.2 %) and costol (5.1 %). Concerning the repellent effect, results revealed that SEO (Seed Essential Oil) was very repellent towards T. castaneum adults, with 100 % repellency after 2 h of exposure. Furthermore, the essential oil exhibited remarkable contact toxicity against T. castaneum (93.3 % of mortality) at the concentration of 10 % (v/v). The median lethal dose (LD50 ) of the topical application of the seed essential oil was 4.4 %. These encouraging outcomes suggested that the essential oil from T. garganica seeds could be considered a potent natural alternative to residual persistent and toxic insecticides.

Pollen analysis of honey from Laghouat region (Algeria)

A microscopic analysis of 41 samples of honey obtained from several locations in the Laghouat region revealed the presence of 98 pollen types belonging to 48 families. Asteraceae, Fabaceae and Nitrariaceae were present in all the samples. Brassicaceae, Rhamnaceae and Apiaceae were identified in more than 80% of the samples. The families with highest diversity of pollen types were Fabaceae and Asteraceae with 13 and 11 types, respectively, Apiaceae and Boraginaceae with five types each. Twenty-seven honey samples (65.85%) were found to be monofloral and the remaining 14 polyfloral. The pollen types from Ziziphus lotus, Peganum harmala, Echium sp., Tamarix sp., Lotus, Eucalyptus sp., Eruca vesicaria and Thapsia garganica appeared as the predominant pollen. Eighteen pollen types were classified as very frequent, present in more than 50% of the samples. The number of pollen types identified per sample ranged between 14 and 40 (mean of 24.41). For the quantitative analysis, the pollen content of the studied honey samples ranged from medium (class II, 48.78% of the samples) to high (class III, 53.65% of the samples), where the pollen density ranged from 26 607 to 660 992 in 10 g of honey, with an average of 160 880 grains per 10 g.

Phytoremediation potential of spontaneous plant species in soils contaminated by hexavalent chromium in Djelfa city (Algeria)

This study aims to quantify hexavalent chromium in wastewater, plants and topsoil in Djelfa city (South of Algeria) in order to better understand the bioaccumulation and phytoremediation potential of eight spontaneous plant species growing in a polluted environment, namely Sisymbrium Irio, Spinacia oleracea, Avena Sativa, Silybum Eburneum, Euphorbia Bupleuroides, Thapsia Garganica, Hertia Cheirifolia and Marrubium Vulgare. Wastewater, soil and spontaneous plant samples were collected near Djelfa’s Oued Mellah valley. Spectrophotometric measurements of hexavalent chromium concentration were used to determine pollution levels and to assess the accumulation potential of studied spontaneous plants. The results showed that in wastewater, soil and plant samples, Cr(VI) concentrations near the tannery upstream were 0.6 mg/L, 44 mg/kg and 6.2 mg/kg respectively. The most significant bioaccumulation potential was recorded with Thapsia Garganica while the highest translocation factor (TF) was found in Marrubium Vulgare. These species could be considered as a promising phytoremediation solution for chromium-polluted soils. According to plant sample enrichment factor (EF), the roots of almost all tested plants were found to be more effective to accumulate Cr(VI) than shoots.

Mipsagargin: The Beginning-Not the End-of Thapsigargin Prodrug-Based Cancer Therapeutics.

Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit Thapsia garganica. In the late 1980s/early 1990s, TG was supplied to multiple independent and collaborative groups. Using this TG, studies documented with a large variety of mammalian cell types that TG rapidly (i.e., within seconds to a minute) penetrates cells, resulting in an essentially irreversible binding and inhibiting (IC50~10 nM) of SERCA 2b calcium uptake pumps. If exposure to 50–100 nM TG is sustained for >24–48 h, prostate cancer cells undergo apoptotic death. TG-induced death requires changes in the cytoplasmic Ca2+, initiating a calmodulin/calcineurin/calpain-dependent signaling cascade that involves BAD-dependent opening of the mitochondrial permeability transition pore (MPTP); this releases cytochrome C into the cytoplasm, activating caspases and nucleases. Chemically unmodified TG has no therapeutic index and is poorly water soluble. A TG analog, in which the 8-acyl groups is replaced with the 12-aminododecanoyl group, afforded 12-ADT, retaining an EC50 for killing of <100 nM. Conjugation of 12-ADT to a series of 5–8 amino acid peptides was engineered so that they are efficiently hydrolyzed by only one of a series of proteases [e.g., KLK3 (also known as Prostate Specific Antigen); KLK2 (also known as hK2); Fibroblast Activation Protein Protease (FAP); or Folh1 (also known as Prostate Specific Membrane Antigen)]. The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing.

Phytochemical Content, Antioxidant and Antimicrobial Effects of Thapsia garganica L. Leaves and Roots Grown Wild in North-west Algeria

Background: Oxygen-centre free radicals and other reactive oxygen species (ROS) are continuously produced in vivo, resulting in cell death and tissues damage. Besides, the increasing resistance to existing antimicrobial agents has become a major problem. The present study aims to evaluate the antioxidant and antimicrobial activities of the Thapsia garganica L. leaves and roots. Methods: Broth dilution and single spore methods were developed and seven microorganisms were used. The evaluation was performed by measuring the diameter of the growth inhibition zones around the holes via the determination of the inhibition percentage of mycelium growth. Result: The determination of the polyphenol contents, total flavonoids and condensed tannins of the aqueous extract for both leaves and roots gave respectively (2.21 mg, 2.63 mg/100 mg gallic acide equivalents), (2.39 mg, 0.49 mg/100 mg catechin equivalent), (0.12 mg, 0.04 mg/100 mg catechin equivalent) in dry matter. The results of antioxidant activity showed that the methanolic, flavonoids and tannins extracts showed a potent scavenging activity with IC50 = 0.41; 0.81; 1.39; 1.80 and 1.90 mg/ml, respectively. As regards for antimicrobial activity, an important inhibition of the proposed extracts has been observed against the tested strains.

From Plant to Patient: Thapsigargin, a Tool for Understanding Natural Product Chemistry, Total Syntheses, Biosynthesis, Taxonomy, ATPases, Cell Death, and Drug Development.

Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. The pronounced cytotoxicity of thapsigargin is caused by highly selective inhibition of the intracellular sarco-endoplasmic Ca2+-ATPase (SERCA) situated on the membrane of the endo- or sarcoplasmic reticulum. Thapsigargin is selective to the SERCA pump and to a minor extent the secretory pathway Ca2+/Mn2+ ATPase (SPCA) pump. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography. These results led to descriptions of the mechanism of action and kinetic properties of SERCA and other ATPases. Inhibition of SERCA depletes Ca2+ from the sarco- and endoplasmic reticulum provoking the unfolded protein response, and thereby has enabled new studies on the mechanism of cell death. Development of protocols for selective transformation of thapsigargin disclosed the chemistry and facilitated total synthesis of the molecule. Conversion of trilobolide into thapsigargin offered an economically feasible sustainable source of thapsigargin, which enables a future drug production. Principles for prodrug development were used by conjugating a payload derived from thapsigargin with a hydrophilic peptide selectively cleaved by proteases in the tumor. Mipsagargin was developed in order to obtain a drug for treatment of cancer diseases characterized by the presence of prostate specific membrane antigen (PSMA) in the neovascular tissue of the tumors. Even though mipsagargin showed interesting clinical effects the results did not encourage funding and consequently the attempt to register the drug has been abandoned. In spite of this disappointing fact, the research performed to develop the drug has resulted in important scientific discoveries concerning the chemistry, biosynthesis and biochemistry of sesquiterpene lactones, the mechanism of action of ATPases including SERCA, mechanisms for cell death caused by the unfolded protein response, and the use of prodrugs for cancer-targeting cytotoxins. The presence of toxins in only some species belonging to Thapsia also led to a major revision of the taxonomy of the genus.

Palynological characterisation of sedra honeys (Ziziphus lotus) produced in Algeria

A melissopalynological study was carried out on 46 samples of Ziziphus lotus honey from Laghouat and Djelfa region (central Algeria). The number of pollen types identified per honey sample ranges between nine and 39 with a mean of 24. These correspond to 52 botanical families with 79 different pollen types in the whole samples. Asteraceae and Fabaceae families were present in all the samples where as Apiaceae, Brassicaceae and Nitrariaceae (Peganum harmala) were identified in more than 90%. Other plant families as Boraginaceae, Cistaceae, Myrtaceae, Oleaceae, Salicaceae or Urticaceae were identified in more than 50% of the samples but frequently as minor pollen. Ziziphus lotus pollen had a mean content of 68.9% (with a range of 45.3% to 93.4%). The secondary pollen types were Ononis natrix, Peganum harmala, Brassica napus, Echium and Olea europaea. Regarding the important pollen it is highlighted the presence Lotus t., Eucalyptus, Pimpinella anisum t., Trifolium t., Eryngium campestre t., Centaurea t., Galega officinalis t., Citrus or Scrophularia t. The sedra honeys of the studied region are characterised by their high content in pollen grains with a mean content of 188 403 grains/10 g. The presence of some pollen types in the pollen spectra of honeys such as Peganum harmala, Thapsia garganica, Launaea, Muscari comosum, Carthamus or Limonium bonduellei together several Asteraceae as Centaurea, Taraxacum, Carduus, Artemisia and Matricaria was proposed as geographical markers of this honey type.

Thapsigargins and induced chemical defence in Thapsia garganica

Thapsigargin and related compounds are produced by Thapsia garganica L. (Apiaceae) and are thought to be a defence compound against herbivory. Thapsigargin inhibits the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) in both vertebrates and invertebrates. This activity is responsible for its potent toxicity, as well as the potential use to treat solid tumours. However, the ecological role and regulation of thapsigargin are not well understood, and the aim of this study was to investigate if thapsigargin biosynthesis was responsive to leaf damage. To test the response to potential leaf damage during a herbivory, greenhouse plants were subjected to clipping to mimic the physical damage. Unclipped versus clipped plants were sampled for chemical analysis and the gene expression for the two known thapsigargin biosynthetic genes (TgTPS2 and TgCYP76AE2) was investigated. Data obtained by LC–ESI–MS/MS were used to perform molecular networking to identify chemical constituents related to thapsigargin and its biosynthesis. The results show a significant change in a plant’s chemical profile after mimicking an herbivory event. Both the chemical analysis and gene expression data show that T. garganica plants can induce the biosynthesis of this class of defence compounds at the site of an attack. Thapsigargins are clearly the dominant defence compounds in these plants, and they seem to be produced through a common biosynthetic pathway with little diversity. This likely means that T. garganica has a relatively simple response to herbivory, as opposed to many other plant species that have been shown to have complex metabolite responses to herbivory.

‘Variations in phenological and functional traits in Thapsia garganica populations in Al Jebel Al Akhdar, Libya’

AbstractThapsia garganica is a herbaceous perennial in the Apiaceae, distributed around the Mediterranean and traditionally used in North Africa as a remedy for arthritis, herpes, hair‐fall, hypertension, rheumatic, eczema and scabies. T. garganica is the source of thapsigargin: known for killing cancer cells. Seven populations were studied in sites differing in aspect and elevation within Al Jebel Al Akhdar in Libya. We studied the within‐population size distribution of individuals, the timing of the phenological events, and vegetative and reproductive traits.Thapsia garganica showed high flexibility of functional traits and shifts in the timing of phenological events in response to elevation and aspect (north‐ or south‐facing slopes). Local soil properties, together with effects due to altitude and aspect, could be direct causes of the observed differences in terms of population size and phenological traits. The phenological patterns detected also provide insights into the species response to climate change. Despite this phenotypic flexibility, and good growth in sites at 300–700 m a. s. l. on south‐facing slopes, most sites in this study have an unstable size‐structure, with few small individuals. This raises concerns about the long‐term persistence of the other populations of this species in Al Jebel Al Akhdar.

Thapsia garganica allelopathic potentialities explored for lettuce growth enhancement and associated weed control

Thapsia garganica phytotoxicity was studied on Lactuca sativa L. and associated weeds, by pulverization of its aqueous extracts (at 10, 20, and 30 %), in pot experiments. To comprehend its mode of action on lettuce, seedlings were grown hydroponically in Hoagland nutrient solution for two months, then the T. garganica leaves aqueous extract was added to the medium for three days. After the harvest, a number of physiological and biochemical parameters had been determined. The antioxidant activity for DPPH (2,2-diphenyl-1-picrylhydrazyl radical) and FRAP (Ferric reducing antioxidant power), and secondary metabolite production were assessed by employing QUENCHER approach. The pulverization treatment was beneficial for lettuce growth, whose length of different organs has been improved at all concentrations. However, it has been very harmful to weeds and in a more important way to monocotyledons, which were totally burned at 30 %, compared to dicotyledons weeds. To allelopathic stress, lettuce developed a defense strategy manifested by a decrease of electrolyte leakage and malondialdehyde content (MDA), an increase in proline content and in polyphenols, flavonoids, flavanols, proanthocyanidins, condensed tannins and carotenoids production. Similarly, a stimulation of the antioxidant activity was recorded, by increasing DPPH free radical-scavenging activity and ferric reducing antioxidant power. For lyase type enzymes (the phenylalanine ammonia-lyase (PAL) and the tyrosine ammonia-lyase (TAL)) activities, an improvement of 25.00 % for the PAL and 38.00 % for the TAL were registered in roots and leaves, respectively. Chlorophyll contents were similarly affected, however the respiration decreased. T. garganica is a species rich in allelochemicals compounds, according to its allelopathic potential. The possibility of using its aqueous extract by spraying shows that it could be an ecofriendly approach to exploit its valuable allelochemicals.

Exploring evolutionary theories of plant defence investment using field populations of the deadly carrot.

There are a number of disparate models predicting variation in plant chemical defences between species, and within a single species over space and time. These can give conflicting predictions. Here we review a number of these theories, before assessing their power to predict the spatial-temporal variation of thapsigargins between and within populations of the deadly carrot (Thapsia garganica). By utilizing multiple models simultaneously (optimum defence theory, growth rate hypothesis, growth-differentiation balance hypothesis, intra-specific framework and resource exchange model of plant defence), we will highlight gaps in their predictions and evaluate the performance of each. Thapsigargins are potent anti-herbivore compounds that occur in limited richness across the different plant tissues of T. garganica, and therefore represent an ideal system for exploring these models. Thapsia garganica plants were collected from six locations on the island of Ibiza, Spain, and the thapsigargins quantified within reproductive, vegetative and below-ground tissues. The effects of sampling time, location, mammalian herbivory, soil nutrition and changing root-associated fungal communities on the concentrations of thapsigargins within these in situ observations were analysed, and the results were compared with our model predictions. The models performed well in predicting the general defence strategy of T. garganica and the above-ground distribution of thapsigargins, but failed to predict the considerable proportion of defences found below ground. Models predicting variation over environmental gradients gave conflicting and less specific predictions, with intraspecific variation remaining less understood. Here we found that multiple models predicting the general defence strategy of plant species could likely be integrated into a single model, while also finding a clear need to better incorporate below-ground defences into models of plant chemical defences. We found that constitutive and induced thapsigargins differed in their regulation, and suggest that models predicting intraspecific defences should consider them separately. Finally, we suggest that in situ studies be supplemented with experiments in controlled environments to identify specific environmental parameters that regulate variation in defences within species.

Thapsigargin induces apoptosis in adrenocortical carcinoma by activating endoplasmic reticulum stress and the JNK signaling pathway: an in vitro and in vivo study.

ObjectiveThapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown.MethodsIn this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells.ResultsThe results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG.ConclusionOur findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.

Use of a temporary immersion bioreactor system for the sustainable production of thapsigargin in shoot cultures of Thapsia garganica

BackgroundThapsigargin and nortrilobolide are sesquiterpene lactones found in the Mediterranean plant Thapsia garganica L. Thapsigargin is a potent inhibitor of the sarco/endoplasmic reticulum calcium ATPase pump, inducing apoptosis in mammalian cells. This mechanism has been used to develop a thapsigargin-based cancer drug first by GenSpera and later Inspyr Therapeutics (Westlake Village, California). However, a stable production of thapsigargin is not established.ResultsIn vitro regeneration from leaf explants, shoot multiplication and rooting of T. garganica was obtained along with the production of thapsigargins in temporary immersion bioreactors (TIBs). Thapsigargin production was enhanced using reduced nutrient supply in combination with methyl jasmonate elicitation treatments. Shoots grown in vitro were able to produce 0.34% and 2.1% dry weight of thapsigargin and nortrilobolide, respectively, while leaves and stems of wild T. garganica plants contain only between 0.1 and 0.5% of thapsigargin and below detectable levels of nortrilobolide. In addition, a real-time reverse transcription PCR (qRT-PCR) study was performed to study the regulatory role of the biosynthetic genes HMG-CoA reductase (HMGR), farnesyl diphosphate synthase (FPPS), epikunzeaol synthase (TgTPS2) and the cytochrome P450 (TgCYP76AE2) of stem, leaf and callus tissues. Nadi staining showed that the thapsigargins are located in secretory ducts within these tissues.ConclusionsShoot regeneration, rooting and biomass growth from leaf explants of T. garganica were achieved, together with a high yield in vitro production of thapsigargin in TIBs.

Effects of gamma irradiation and comparison of different extraction methods on sesquiterpene lactone yields from the medicinal plant Thapsia garganica L. (Apiaceae)

Ethnopharmacological relevanceThapsia garganica L. roots are used in Algerian traditional medicine for a number of ailments. It is used in a poultice as an antitussive treatment of acute bronchitis and pneumonia, in preparations with milk or oil taken orally to treat common lung diseases, and with the direct application of root sections for the soothing of dental pains. Aim of the studyThe objective of this study was to evaluate the combined effect of microwave assisted extraction and gamma irradiation on sesquiterpene lactones in T. garganica extracts Materials and methodsTo evaluate the combined effect of microwave assisted extraction and gamma irradiation on the highly bioactive compounds found in extracts of Algerian T. garganica, samples from different locations in Algeria were prepared by extraction from dried leaf and root samples of dried plant material, using different extraction methods Quantification of the compounds of interest was done using an HPLC. The antioxidant activity extracts was determined using the two free radical scavenging assays: the 2,2-diphenyl-picryl-hydrazyl (DPPH) and the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS). ResultsIt was found that location and extraction method had significant impact on the phytochemical composition of extracts. Gamma irradiation was found to have no effect on the phytochemical composition of the plant extracts or on their antioxidant properties. ConclusionThe study has shown that microwave assisted extraction is an effective method for investigating chemical compounds in T. garganica and the results support the notion that gamma irradiation for sterilisation do not alter the chemical composition.The authors wish to clarify that we cannot recommend the usage of any parts of T. garganica, in any form, for any remedy due to its very high toxicity.

Essential Oil Composition of the Root Bark of Thapsia garganica (L.) Growing in Northwestern Algeria

Thapsia garganica (L.) is a perennial plant that belongs to the family Apiaceae and is widely used in Saïda Province, Algeria because of its important bioactive properties. Traditionally, the root bark of T. garganica is used alone or mixed with olive oil as an analgesic, diuretic, purgative and emmenagogue. In this study, essential oils were extracted from the root bark of T. garganica by hydrodistillation and characterized by gas chromatography mass spectrometry (CG-MS). Thirty-seven compounds representing 97.01 % of the total composition of the oil were identified by CG-MS. Among these compounds, myristicin, β-thujone, and elemicin were the dominant components contributing to 15.07 %, 14.86 %, and 13.06 % of the total, respectively. There have been no other reports of β-thujone as a major constituent in T. garganica.

Localization and in-Vivo Characterization of Thapsia garganica CYP76AE2 Indicates a Role in Thapsigargin Biosynthesis.

The Mediterranean plant Thapsia garganica (dicot, Apiaceae), also known as deadly carrot, produces the highly toxic compound thapsigargin. This compound is a potent inhibitor of the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase calcium pump in mammals and is of industrial importance as the active moiety of the anticancer drug mipsagargin, currently in clinical trials. Knowledge of thapsigargin in planta storage and biosynthesis has been limited. Here, we present the putative second step in thapsigargin biosynthesis, by showing that the cytochrome P450 TgCYP76AE2, transiently expressed in Nicotiana benthamiana, converts epikunzeaol into epidihydrocostunolide. Furthermore, we show that thapsigargin is likely to be stored in secretory ducts in the roots. Transcripts from TgTPS2 (epikunzeaol synthase) and TgCYP76AE2 in roots were found only in the epithelial cells lining these secretory ducts. This emphasizes the involvement of these cells in the biosynthesis of thapsigargin. This study paves the way for further studies of thapsigargin biosynthesis.

Domesticating deadly carrots: Predicting the biosynthetic pathway of thapsigargins for the treatment of solid tumors

Thapsigargin, a guaianolide sesquiterpene lactone, is the active component of a pro-drug currently in phase 2 of clinical trials for the treatment of solid tumours. Thapsigargin is currently only being isolated from Thapsia garganica L. (Apiaceae); a member of the taxonomically complex genus Thapsia L. found in the Mediterranean. Thapsia species do not grow well out of their natural habitat and on-going research seeks to solve the potential resource problem for Mipsagargin, a new thapsigargin derived drug, by transferring the biosynthetic pathway to other heterologous hosts for efficient production [1]. Plant material of Thapsia garganica has been collected from around the species' Mediterranean range, as part of a revision of the genus. The amount of thapsigargin and other closely related guaianolides was quantified between individuals across its range, in planta and during the growing season. Secondly the expression levels of the terpene synthases TgTPS1 and TgTPS2, as well as a cytochrome P450, thought to be involved in the biosynthesis of thapsigargin, were investigated. These tests have also been carried out in conjunction with soil analyses to test if fluctuations in the levels of thapsigargin can be linked to environmental factors. Thapsigargin has been found to be extremely variable over its geographical distribution even over small areas. Lastly, to see whether candidates for the biosynthesis of thapsigargin could shed light on where the compound is made within the plant, root sections have been investigated from greenhouse plants provided by ThapsIbiza. Using light microscopy and MALDI-imaging epithelial cells containing thapsigargin and surrounding secretory channels within the vascular cambium were observed, indicating for the first time that this is the localisation of thapsigargin biosynthesis. It is hoped that these results will fast track the discovery of new enzymes involved in the biosynthetic pathway of thapsigargin.

Role of endoplasmic reticulum stress in drug-induced toxicity.

Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.