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Abstract Background The demand for natural product-based treatment options for livestock is increasing by animals’ owners, veterinarians and policy makers. But at the same time, the traditional knowledge about it is at risk of falling into oblivion in Europe. The present study recorded this knowledge for the linguistically and geographically interesting Swiss canton of Valais. Method Open, semi-structured interviews were used to collect detailed information on formulations and applications, including plant species and natural substances, origin of material, extraction and preparation of herbal products, indication and type of application, dosage, sources of knowledge, frequency of usage and self-assessment of the treatment. Results and discussion In the course of 43 interviews, 173 homemade single species herbal remedy report (HSHR) were recorded. They included 53 plant species from 30 botanical families. Plant species from the botanical families of Asteraceae, Rubiaceae and Cupressaceae were mentioned the most, while the most frequently documented plant species were Coffea arabica L., Juniperus sabina L., Arnica montana L. and Matricaria chamomilla L. For the 173 HSHR, a total of 215 uses were mentioned, most of which were for the treatment of gastrointestinal and metabolic disorders, followed by skin lesions and genito-urinary tract problems. Regional peculiarities emerged, such as the use of Leontopodium alpinum Cass. for diarrhea in the French-speaking Valais, while Matricaria chamomilla and Camellia sinensis L. were used in the German-speaking part instead. In comparison with other regions of Switzerland, 10 plants were reported for the first time, including Juniperus sabina with 18 use reports. Conclusion The daily use on farms and the high satisfaction of farmers with homemade herbal remedies demonstrate their high practical relevance. In conclusion, the traditional regional knowledge about the use of medicinal plants is not only a cultural heritage worth protecting, but also an essential resource for the further development of European veterinary medicine.

Herbs rich in secondary metabolites may possess beneficial properties in livestock nutrition and health. 49 Polygonaceae species of European mountain regions were included in a qualitative systematic review based on the methodological framework of the PRISMA statement. 174 relevant publications were identified. They comprised 231 in vitro and 163 in vivo experiments with cattle, sheep, goats, poultry, pigs, and rodents. For 16 Polygonaceae species no reports were found. Fagopyrum esculentum and Fagopyrum tataricum showed potential as anti-inflammatory, antioxidative and metabolic modifying herbs and feeds improving intake and nitrogen conversion in broiler as well as milk quality and ruminal biotransformation in dairy cows. Polygonum aviculare was promising as an antimicrobial and anti-inflammatory drug or feed, improving performance and affecting ruminal biotransformation in sheep, and Polygonum bistorta as an anti-inflammatory drug or feed, improving performance in broiler and mitigating methane emissions in ruminants. Rumex obtusifolius showed potential as an antibacterial drug or feed improving ruminal biotransformation and preventing bloating in cows, while Rumex acetosa and Rumex acetosella had antimicrobial and anti-inflammatory properties. Furthermore, Polygonum minus, Polygonum persicaria, Rumex crispus and Rumex patientia possess interesting anti-inflammatory and antimicrobial activities. In conclusion, some Polygonaceae species show relevant properties that might be useful to prevent and treat livestock diseases, combined with nutritional benefits in performance, product quality, lowering ruminal methane and ammonia formation and transferring omega-3 fatty-acids from feed to tissue. The potential of such multifunctional plants for a holistic integration of veterinary, nutritional and ecological perspectives under a one-health approach of livestock management is discussed.

Coproporphyrin I (CPI) and III (CPIII) are discussed as biomarkers for organic anion transporting polypeptides (OATPs). We report on CPI and CPIII levels in wildtype, rSlco2b1-knockout, and SLCO2B1-humanized rats at baseline and after administration of atorvastatin, an inhibitor of the CPIII-specific rOATP2B1/hOATP2B1 and the CPI/CPIII-transporting rOATP1B2. OATP-inhibition by atorvastatin leads to significantly increased CPI and CPIII serum levels. However, basal CP serum levels in rSlco2b1-knockout animals were significantly lower (CPI), or unaffected (CPIII). In the presence of atorvastatin, this genotype effect was abolished. In conclusion, our results indicate an unexpected impact of OATP2B1 on CP serum levels in rats.

The aims of the present study were (i) to characterize the dichloromethane extract of the fresh aerial parts of S. somalensis, cultivated in Liguria (Italy), (ii) to quantify carnosic acid production and (iii) to find an eco-friendly alternative approach to control diseases caused by phytopathogenic fungi. The phytochemical investigation yielded several known terpenoids, as well as a diterpene, 4α,9α-epoxy-2H-dibenzo[a,d]cyclohepten-7(5H)-one, not previously described as a plant metabolite before. The results showed a noteworthy quantity of carnosic acid (113.90 µg/mg of dried extract). The potential antifungal activity of the plant surface extract and carnosic acid against five phytopathogenic fungi (Colletotrichum coccodes, Fusarium oxysporum, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani) was considered. A complete inhibition of C. coccodes, S. sclerotiorum and R. solani mycelium growth was observed by carnosic acid at 500 µg/mL. High inhibition values were observed against B. cinerea and F. oxysporum compared to reference active ingredients. Four different B. cinerea strains exhibited a pronounced sensitivity to carnosic acid, as well as those originating from agricultural crop scenarios where a high load of active ingredient for gray mold control was historically adopted. Additionally, the formation and development of the germinative tube in B. cinerea were greatly slowed down.

Introduction: Treatment with cannabis extracts for a variety of diseases has gained popularity. However, differences in herb-drug interaction potential of extracts from different plant sources are poorly understood. In this study, we provide a characterization of cannabis extracts prepared from four cannabis chemotypes and an in vitro assessment of their Cytochrome P450 (CYP)-mediated herb-drug interaction profiles. Methods: Plant extracts were either commercially obtained or prepared using ethanol as solvent, followed by overnight decarboxylation in a reflux condenser system. The extracts were characterized for their cannabinoid content using NMR and HPLC-PDA-ELSD-ESIMS. CYP inhibition studies with the cannabis extracts and pure cannabinoids (tetrahydrocannabinol [THC] and cannabidiol [CBD]) were performed using pooled, mixed gender human liver microsomes. Tolbutamide and testosterone were used as specific substrates to assess the inhibitory potential of the extracts on CYP2C9 and CYP3A4, and the coumarinic oral anticoagulants warfarin, phenprocoumon, and acenocoumarol were studied as model compounds since in vivo herb-drug interactions have previously been reported for this compound class. Results: In accordance with the plant chemotypes, two extracts were rich in THC and CBD (at different proportions); one extract contained mostly CBD and the other mostly cannabigerol (CBG). Residual amounts of the corresponding acids were found in all extracts. The extracts with a single major cannabinoid (CBD or CBG) inhibited CYP2C9- and CYP3A4-mediated metabolism stronger than the extracts containing both major cannabinoids (THC and CBD). The inhibition of CYP3A4 and CYP2C9 by the extract containing mostly CBD was comparable to their inhibition by pure CBD. In contrast, the inhibitory potency of extracts containing both THC and CBD did not correspond to the combined inhibitory potency of pure THC and CBD. Although being structural analogs, the three coumarin derivatives displayed major differences in their herb-drug interaction profiles with the cannabis extracts and the pure cannabinoids. Conclusion: Despite the fact that cannabinoids are the major components in ethanolic, decarboxylated cannabis extracts, it is difficult to foresee their herb-drug interaction profiles. Our in vitro data and the literature-based evidence on in vivo interactions indicate that cannabis extracts should be used cautiously when co-administered with drugs exhibiting a narrow therapeutic window, such as coumarinic anticoagulants, regardless of the cannabis chemotype used for extract preparation. Keywords: Cannabinoids, Chemotypes, Vitamin K antagonists, CYP-mediated herb-drug interactions, Coumarinic oral anticoagulants, In vitro CYP inhibition assays, LC-MS/MS, Author(s): Andrea Treyer [a]; Jakob K. Reinhardt [a]; Daniela Elisabeth Eigenmann [b]; Mouhssin Oufir [a,c]; Matthias Hamburger [a] Introduction Cannabis is one of the earliest psychoactive plants that were cultivated [...]

Introduction: Treatment with cannabis extracts for a variety of diseases has gained popularity. However, differences in herb-drug interaction potential of extracts from different plant sources are poorly understood. In this study, we provide a characterization of cannabis extracts prepared from four cannabis chemotypes and an in vitro assessment of their Cytochrome P450 (CYP)-mediated herb-drug interaction profiles. Methods: Plant extracts were either commercially obtained or prepared using ethanol as solvent, followed by overnight decarboxylation in a reflux condenser system. The extracts were characterized for their cannabinoid content using NMR and HPLC-PDA-ELSD-ESIMS. CYP inhibition studies with the cannabis extracts and pure cannabinoids (tetrahydrocannabinol [THC] and cannabidiol [CBD]) were performed using pooled, mixed gender human liver microsomes. Tolbutamide and testosterone were used as specific substrates to assess the inhibitory potential of the extracts on CYP2C9 and CYP3A4, and the coumarinic oral anticoagulants warfarin, phenprocoumon, and acenocoumarol were studied as model compounds since in vivo herb-drug interactions have previously been reported for this compound class. Results: In accordance with the plant chemotypes, two extracts were rich in THC and CBD (at different proportions); one extract contained mostly CBD and the other mostly cannabigerol (CBG). Residual amounts of the corresponding acids were found in all extracts. The extracts with a single major cannabinoid (CBD or CBG) inhibited CYP2C9- and CYP3A4-mediated metabolism stronger than the extracts containing both major cannabinoids (THC and CBD). The inhibition of CYP3A4 and CYP2C9 by the extract containing mostly CBD was comparable to their inhibition by pure CBD. In contrast, the inhibitory potency of extracts containing both THC and CBD did not correspond to the combined inhibitory potency of pure THC and CBD. Although being structural analogs, the three coumarin derivatives displayed major differences in their herb-drug interaction profiles with the cannabis extracts and the pure cannabinoids. Conclusion: Despite the fact that cannabinoids are the major components in ethanolic, decarboxylated cannabis extracts, it is difficult to foresee their herb-drug interaction profiles. Our in vitro data and the literature-based evidence on in vivo interactions indicate that cannabis extracts should be used cautiously when co-administered with drugs exhibiting a narrow therapeutic window, such as coumarinic anticoagulants, regardless of the cannabis chemotype used for extract preparation.

Guidelines for preclinical drug development reduce the occurrence of arrhythmia-related side effects. Besides ample evidence for the presence of arrhythmogenic substances in plants, there is no consensus on a research strategy for the evaluation of proarrhythmic effects of herbal products. Here, we propose a cardiac safety assay for the detection of proarrhythmic effects of plant extracts based on the experimental approaches described in the Comprehensive In vitro Proarrhythmia Assay (CiPA). Microelectrode array studies (MEAs) and voltage sensing optical technique on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were combined with ionic current measurements in mammalian cell lines, In-silico simulations of cardiac action potentials (APs) and statistic regression analysis. Proarrhythmic effects of 12 Evodia preparations, containing different amounts of the hERG inhibitors dehydroevodiamine (DHE) and hortiamine were analysed. Extracts produced different prolongation of the AP, occurrence of early after depolarisations and triangulation of the AP in hiPSC-CMs depending on the contents of the hERG inhibitors. DHE and hortiamine dose-dependently prolonged the field potential duration in hiPSC-CMs studied with MEAs. In-silico simulations of ventricular AP support a scenario where proarrhythmic effects of Evodia extracts are predominantly caused by the content of the selective hERG inhibitors. Statistic regression analysis revealed a high torsadogenic risk for both compounds that was comparable to drugs assigned to the high-risk category in a CiPA study.

Pre-clinical studies suggest that extracts prepared from the fruits of Vitex agnus castus (VAC) interact with dopamine D2 receptors, leading to reduced prolactin secretion. In previous experiments, dopaminergic activity was mostly evaluated using radioligand binding assays or via the inhibition of prolactin release from rat pituitary cells. Diterpenes featuring a clerodadienol scaffold were identified as major active compounds, but no conclusive data regarding their potency and intrinsic activity are available. Utilising advances in chromatography, we re-examined this topic using HPLC-based tracking of bioactivity via microfractionation of the VAC extract Ze 440. Using a cAMP-based assay, we measured dopaminergic activity in CHO-K1 cells that overexpress the human D2 receptor. Six diterpenes were isolated from two active HPLC microfractions. Viteagnusin I emerged as the most potent diterpene (EC50: 6.6 µM), followed by rotundifuran (EC50: 12.8 µM), whereas vitexilactone was inactive (EC50: >50 µM). Interestingly, triterpenes were also identified as active, with 3-epi-maslinic acid being the most active compound (EC50: 5.1 µM). To better understand these interactions at the molecular level, selected diterpenes and triterpenes were analysed through molecular docking against D2 receptor structures. Our data show that the dopaminergic activity of VAC diterpenes seems to depend on the configuration and on ring substitution in the side chain. This study also highlights for the first time the dopaminergic contribution of triterpenes such as 3-epi-maslinic acid. [ABSTRACT FROM AUTHOR]

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.

Abstract Three new compounds (1–3) with unusual skeletons were isolated from the n-hexane extract of the air-dried aerial parts of Hypericum scabrum. Compound 1 represents the first example of an esterified polycyclic polyprenylated acylphloroglucinol that features a unique tricyclo-[4.3.1.11,4]-undecane skeleton. Compound 2 is a fairly simple MPAP, but with an unexpected cycloheptane ring decorated with prenyl substituents, and compound 3 has an unusual 5,5-spiroketal lactone core. Their structures were determined by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, HRESI-TOFMS). Absolute configurations were established by ECD calculations, and the absolute structure of 2 was confirmed by a single crystal determination. Plausible biogenetic pathways of compounds 1–3 were also proposed. The in vitro antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense and Plasmodium falciparum and cytotoxicity against rat myoblast (L6) cells were determined. Compound 1 showed a moderate activity against T. brucei and P. falciparum, with IC50 values of 3.07 and 2.25 μM, respectively.

The aims of the present study were (i) to characterize the dichloromethane extract of the fresh aerial parts of S. somalensis, cultivated in Liguria (Italy), (ii) to quantify carnosic acid production and (iii) to find an eco-friendly alternative approach to control diseases caused by phytopathogenic fungi. The phytochemical investigation yielded several known terpenoids, as well as a diterpene, 4α,9α-epoxy-2H-dibenzo[a,d]cyclohepten-7(5H)-one, not previously described as a plant metabolite before. The results showed a noteworthy quantity of carnosic acid (113.90 µg/mg of dried extract). The potential antifungal activity of the plant surface extract and carnosic acid against five phytopathogenic fungi (Colletotrichum coccodes, Fusarium oxysporum, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani) was considered. A complete inhibition of C. coccodes, S. sclerotiorum and R. solani mycelium growth was observed by carnosic acid at 500 µg/mL. High inhibition values were observed against B. cinerea and F. oxysporum compared to reference active ingredients. Four different B. cinerea strains exhibited a pronounced sensitivity to carnosic acid, as well as those originating from agricultural crop scenarios where a high load of active ingredient for gray mold control was historically adopted. Additionally, the formation and development of the germinative tube in B. cinerea were greatly slowed down. [ABSTRACT FROM AUTHOR]

Summary: Globally, more than six million people are infected with Trypanosoma cruzi, the causative protozoan parasite of the vector-borne Chagas disease (CD). We conducted a cross-sectional ethnopharmacological field study in Bolivia among different ethnic groups where CD is hyperendemic. A total of 775 extracts of botanical drugs used in Bolivia in the context of CD and botanical drugs from unrelated indications from the Mediterranean De Materia Medica compiled by Dioscorides two thousand years ago were profiled in a multidimensional assay uncovering different antichagasic natural product classes. Intriguingly, the phylobioactive anthraquinone hotspot matched the antichagasic activity of Senna chloroclada, the taxon with the strongest ethnomedical consensus for treating CD among the Izoceño-Guaraní. Testing common 9,10-anthracenedione derivatives in T. cruzi cellular infection assays demarcates hydroxyanthraquinone as a potential antichagasic lead scaffold. Our study systematically uncovers in vitro antichagasic phylogenetic hotspots in the plant kingdom as a potential resource for drug discovery based on ethnopharmacological hypotheses.

Bryophyllum pinnatum has been used in the treatment of premature labor, first in anthroposophic hospitals and, recently, in conventional settings as an add-on medication. In vitro work with hTERT human myometrial cells showed that B. pinnatum leaf press juice inhibits the increase of intracellular free calcium concentration induced by oxytocin, a hormone known to play a role in labor. Our aim was to identify fractions/compounds in B. pinnatum press juice that contribute to this inhibitory effect, and to investigate their effect on oxytocin-driven activation of the MAPK cascade. Several fractions/compounds from B. pinnatum press juice led to a concentration-dependent decrease of oxytocin-induced increase of intracellular free calcium concentration, but none of them was as strong as B. pinnatum press juice. However, the combination of a bufadienolide and a flavonoid-enriched fraction was as effective as B. pinnatum press juice, and their combination had a synergistic effect. B. pinnatum press juice inhibited oxytocin-driven activation of MAPKs SAPK/JNK and ERK1/2, an effect also exerted by the bufadienolide-enriched fraction. The effect of B. pinnatum press juice on oxytocin-induced signaling pathways was comparable to that of the oxytocin-receptor antagonist and tocolytic agent atosiban. Our findings further substantiate the use of B. pinnatum press juice preparations in the treatment of preterm labor.

In a screening of Sudanese medicinal plants for antiprotozoal activity, the chloroform fractions obtained by liquid-liquid partitioning from ethanolic extracts of fruits of Croton gratissimus var. gratissimus and stems of Cuscuta hyalina Roth ex Schult. exhibited in vitro activity against axenically grown Leishmania donovani amastigotes. This antileishmanial activity was localized by HPLC-based activity profiling. Targeted preparative isolation afforded flavonoids 1–6, 3-methoxy-4-hydroxybenzoic acid (7), and benzyltetrahydroisoquinoline alkaloids laudanine (8) and laudanosine (9) from C. gratissimus, and pinoresinol (10), isorhamnetin (11), (-)-pseudosemiglabrin (12), and kaempferol (13) from C. hyalina. The antiprotozoal activity of 1–13 against L. donovani (axenic and intracellular amastigotes), Trypanosoma brucei rhodesiense (bloodstream forms), and Plasmodium falciparum (erythrocytic stages), and the cytotoxicity in L6 murine myoblast cells were determined in vitro. Quercetin-3,7-dimethylether (6) showed the highest activity against axenic L. donovani (IC50, 4.5 µM; selectivity index [SI], 12.3), P. falciparum (IC50, 7.3 µM; SI, 7.6), and T. b. rhodesiense (IC50, 2.4 µM; SI, 23.2). The congener ayanin (2) exhibited moderate antileishmanial (IC50, 8.2 µM; SI, 12.2), antiplasmodial (IC50, 7.8 µM; SI, 12.9), and antitrypanosomal activity (IC50, 11.2 µM; SI, 8.9). None of the compounds showed notable activity against the intramacrophage form of L. donovani.

Neglected tropical diseases are major health hazards in developing countries. Annually, up to 30 million people are affected by either Chagas disease, African trypansomiasis or leishmaniasis, and more than 200 million by malaria. Most of the currently available drugs have drawbacks in terms of toxicity, limited oral availability, development of resistance, or non-affordability. Tropical plants of the arid zones are a treasure chest for the discovery of bioactive secondary metabolites. This study aims to compile Sudanese medicinal plants, validate their antiprotozoal activities, and identify active molecules. We have performed a survey of medicinal plants of Sudan and selected 62 that are being used in Sudanese traditional medicine. From these, we collected materials such as leaves, stem, bark, or fruit. The plant materials were extracted in 70% ethanol and further fractionated by liquid-liquid partitioning using solvents of increasing polarity. This resulted in a library of 235 fractions. The library was tested in vitro against Plasmodium falciparum (erythrocytic stages), Trypanosoma brucei rhodesiense (bloodstream forms), Trypanosoma cruzi (intracellular amastigotes), and Leishmania donovani (axenic amastigotes). Active fractions were also tested for cytotoxicity. Of the 235 fractions, 125 showed growth inhibitory activity >80% at 10 μg/ml, and >50% at 2 μg/ml against at least one of the protozoan parasites. Plasmodium falciparum was the most sensitive of the parasites, followed by T. b. rhodesiense and L. donovani. Only few hits were identified for T. cruzi, and these were not selective. Contrary to expectation based on phylogeny, but in agreement with previous results, a large number of extracts displayed mutual activity against T. brucei and P. falciparum. HPLC-based activity profiling for selected active extracts was performed to identify the bioactive principles. Active compounds identified by dereplication were guieranone A from Guiera senegalensis J.F.Gmel.; pseudosemiglabrin from Tephrosia apollinea (Delile) DC; ellagic acid and quercetin from Terminalia leiocarpa (DC.) Baill.; and catechin, ethyl gallate, and epicatechin gallate from Vachellia nilotica (L.) P.J.H.Hurter & Mabb. Also the extracts of Croton gratissimus var. gratissimus and Cuscuta hyalina Roth ex Schult. exhibited promising antitrypanosomatid activity. This assessment provides a comprehensive overview of Sudanese medicinal plants and supports the notion that they are a potential source of bioactive molecules against protozoan parasites.

Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our own research, how these goals can be achieved. Methods: An in-house technology platform comprising pre-formatted extract libraries in 96-well format, miniaturized tracking of activity in extracts via HPLC-activity profiling, structure elucidation with microprobe NMR, and in vitro and in vivo pharmacological methods were used. Results: Piperine was identified as a new scaffold for allosteric GABAA receptor modulators with in vivo activity that interacts at a benzodiazepine-independent binding site. Selectivity and potency were improved by iterative optimization towards synthetic piperine analogues. Dehydroevodiamine and hortiamine from the traditional Chinese herbal drug Evodiae fructus were identified as potent hERG channel blockers in vitro. The compounds induced torsades de pointes arrhythmia in animal models. Conclusions: The allosteric binding site for piperine analogues remains to be characterized and cardiac risks of herbal drugs need to be further evaluated to ensure consumer safety.

The need for novel drugs for the treatment of autoimmune diseases is high, since available pharmaceuticals often have substantial side effects and limited efficacy. Natural products are a good starting point in the development of immunosuppressive leads. Since enhanced T cell proliferation is a common feature of autoimmune diseases, we investigated the T cell proliferation inhibitory potential of an extract library of plants used in traditional Chinese medicine. Using a newly established cell-based screening platform, an ethyl acetate extract of Artemisia argyi H.Lév. & Vaniot (Asteraceae, A. argyi) was found to suppress the proliferation of human primary T lymphocytes in vitro in an IL-2-dependent manner. Flow cytometry- and ELISA-based techniques further demonstrated that the A. argyi extract reduced the activation and function of T cells. Transcription factor analysis and flow cytometric calcium influx investigations indicated that the immunomodulatory effect was based on specific modification of T cell signaling in a non-cytotoxic manner which is mediated via the NFAT pathway and a non-sequestrant inhibition of the calcium influx. A series of guaianolide and seco-guaianolide sesquiterpene lactones, as well as a flavonoid, were identified in a previous study as the bioactive compounds in the A. argyi extract. The effects of these bioactive compounds were compared to those of the crude extract. The tested sesquiterpene lactones act via the transcription factor NFAT and NF-κB, thereby exhibiting their immunosuppressive potential, but have an overall effect on T cell biology on a more-downstream level than the crude A. argyi extract.