Phytochemical study of Seriphidium khorassanicum (syn. Artemisia khorassanica) aerial parts: sesquiterpene lactones with anti-protozoal activity.

Two new eudesmane-type sesquiterpene lactones, 1ß,3α,8α-trihydroxy-11ß,13-dihydroeudesma-4(15)-en-12,6α-olide (1) and 1ß,4α,8α-trihydroxy-11ß,13-dihydroeudesma-12,6α-olide (2), and an unprecedented elemane-type sesquiterpene lactone, 1ß,2ß,8α-trihydroxy-11ß,13-dihydroelema-12,6α-olide (3) along with a known eudesmanolide artapshin (4) were isolated from Seriphidium khorassanicum. Structures were elucidated by NMR, HR-ESI-MS, and ECD spectral data analysis. The anti-protozoal activity was evaluated against Leishmania major promastigotes and amastigote-infected macrophages. They showed dose- and time-dependent activity against L. major amastigotes with IC50 values in the range of 4.9 to 25.3 µM being favourably far below their toxicity against normal murine macrophages with CC50 values ranging from 432.5 to 620.7 µM after 48 h of treatment. Compound 3 exhibited the strongest activity and the highest selectivity index (SI) with IC50 of 4.9 ± 0.6 µM and SI of 88.2 comparable with the standard drug, meglumine antimoniate (Glucantime), with IC50 and SI values of 15.5 ± 2.1 µM and 40.0, respectively.

Fatimanols Y and Z: two neo-clerodane diterpenoids from Teucrium yemense.

Teucrium yemense (Defl.), a medicinal plant, grows in Yemen and Saudi Arabia and is also referred to as Reehal Fatima. The plant has a long history of use in these regions for the treatment of diabetes, rheumatism, and renal conditions. Phytochemical investigation of the aerial parts of T. yemense yielded two previously undescribed neo-clerodane diterpenoids, namely fatimanols Y and Z (1 and 2) along with the known teulepicephin (3), 8-acetylharpagide (4) and teucardosid (5). Structure elucidation was accomplished from their 1D and 2D NMR, ECD, and MS characteristics as well as by comparing them to related reported compounds. The new molecules expand understanding of secondary metabolites of this genus. Compounds 1-5 did not show antimicrobial activity against various bacterial and fungal strains.

Isolation of Two Plasticizers, Bis(2-ethylhexyl) Terephthalate and Bis(2-ethylhexyl) Phthalate, from Capparis spinosa L. Leaves.

Many plants have been known to be contaminated and accumulate plasticizers from the environment, including water sources, soil, and atmosphere. Plasticizers are used to confer elasticity and flexibility to various fiber and plastic products. Consumption of plasticizers can lead to many adverse effects on human health, including reproductive and developmental toxicity, endocrine disruption, and cancer. Herein, we report for the first time that two plasticizers, bis(2-ethylhexyl) terephthalate (DEHT) and bis(2-ethylhexyl) phthalate (DEHP), have been isolated from the leaves of Capparis spinosa L. (the caper bush), a plant that is widely used in food seasonings and traditional medicine. 297 mg/kg of DEHT and 48 mg/kg of DEHP were isolated from dried and grounded C. spinosa L. leaves using column chromatography and semi-preparative high-performance liquid chromatography. Our study adds to the increase in the detection of plasticizers in our food and medicinal plants and to the alarming concern about their potential adverse effects on human health.

Quality Consistency of Herbal Products: Chemical Evaluation.

The widespread utility of herbal products has been rising considerably worldwide, including both developed and developing countries, leading to the rapid growth of their availability in the United States and globally. This substantial increase in consumption of herbal products has witnessed the emergence of adverse effects upon oral administration of certain of these products, and thus has raised safety concerns. The adverse effects caused by the consumption of certain botanical medicines occur primarily as a result of the poor quality of plant raw materials or the finished products, which inherently may affect safety and/or efficacy. The poor quality of some herbal products can be attributed to a lack of proper quality assurance and quality control. A high demand for herbal products that surpasses production, combined with a desire for maximizing profits, along with a lack of rigorous quality control within some manufacturing facilities have led to the emergence of quality inconsistencies. The underlying causes for this involve the misidentification of plant species, or their substitution, adulteration, or contamination with harmful ingredients. Analytical assessments have revealed there to be frequent and significant compositional variations between marketed herbal products. The inconsistency of the quality of herbal products can be ascribed essentially to the inconsistency of the botanical raw material quality used to manufacture the products. Thus, the quality assurance and the quality control of the botanical raw materials is may contribute significantly to improving the quality and consistency of the quality of the end products. The current chapter focuses on the chemical evaluation of quality and consistency of herbal products, including botanical dietary supplements. Different techniques, instruments, applications, and methods used in identifying, quantifying, and generating chemical fingerprints and chemical profiles of the ingredients of the herbal products will be described. The strengths and weaknesses of the various techniques available will be addressed. Limitations of the other approaches including morphological or microscopic analysis and DNA-based analysis will be presented.

Evaluation of the Herb-Drug Interaction (HDI) Potential of Zingiber officinale and Its Major Phytoconstituents.

Ginger is currently one of the most popular herbs commonly added to diverse foods, beverages, and dietary supplements. We evaluated the ability of a well-characterized ginger extract, and several of its phytoconstituents, to activate select nuclear receptors as well as modulate the activity of various cytochrome P450s and ATP-binding cassette (ABC) transporters because phytochemical-mediated modulation of these proteins underlies many clinically relevant herb-drug interactions (HDI). Our results revealed ginger extract activated the aryl hydrocarbon receptor (AhR) in AhR-reporter cells and pregnane X receptor (PXR) in intestinal and hepatic cells. Among the phytochemicals investigated, (S)-6-gingerol, dehydro-6-gingerdione, and (6S,8S)-6-gingerdiol activated AhR, while 6-shogaol, 6-paradol, and dehydro-6-gingerdione activated PXR. Enzyme assays showed that ginger extract and its phytochemicals dramatically inhibited the catalytic activity of CYP3A4, 2C9, 1A2, and 2B6, and efflux transport capabilities of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dissolution studies with ginger extract conducted in biorelevant simulated intestinal fluid yielded (S)-6-gingerol and 6-shogaol concentrations that could conceivably exceed cytochrome P450 (CYP) IC50 values when consumed in recommended doses. In summary, overconsumption of ginger may disturb the normal homeostasis of CYPs and ABC transporters, which in turn, may elevate the risk for HDIs when consumed concomitantly with conventional medications.

Is Baikiain in Tara Flour a Causative Agent for the Adverse Events Associated with the Recalled Frozen French Lentil & Leek Crumbles Food Product? - A Working Hypothesis.

The French Lentil & Leek Crumbles frozen food product was recently recalled due to reports of gastrointestinal issues. So far, 393 adverse illness complaints and 133 hospitalizations have been reported from consumption of this food, and the tara (Tara spinosa) protein flour ingredient is hypothesized to be responsible. A multipronged approach resulted in identification of (S)-(-)-baikiain in tara as a compound of interest due to its abundance, possible metabolic fate, and close resemblance to irreversible inhibitors of L-pipecolate oxidase. Oral administration of baikiain in ND4 mice showed a statistically significant increase in blood ALT levels and a reduction in liver GSH.

Revisiting the Flora of Saudi Arabia: Phytochemical and Biological Investigation of the Endangered Plant Species Euphorbia saudiarabica.

Euphorbia plants have a significant place in traditional medicine due to their numerous therapeutic properties, including their anti-tumor effects, which have been observed in several species. In the current study, a phytochemical investigation of Euphorbia saudiarabica methanolic extract led to the isolation and characterization of four secondary metabolites from the chloroform (CHCl3) and ethyl acetate (EtOAc) fractions, which are reported for the first time in this species. One of the constituents, saudiarabicain F (2), is a rare C-19 oxidized ingol-type diterpenoid that has not been previously reported. The structures of these compounds were determined by extensive spectroscopic (HR-ESI-MS, 1D and 2D NMR) analyses. The anticancer properties of the E. saudiarabica crude extract, its fractions and its isolated compounds were examined against several cancer cells. The active fractions were evaluated for their effects on cell-cycle progression and apoptosis induction using flow cytometry. Furthermore, RT-PCR was employed to estimate the gene-expression levels of the apoptosis-related genes. It was demonstrated that the E. saudiarabica CHCl3 and EtOAc fractions suppressed the proliferation of the cancer cells. The MCF-7 cells were the most sensitive to both fractions, with IC50 values of 22.6 and 23.2 µg/mL, respectively. Notably, both fractions caused cell-cycle arrest in the G2/M phase of the treated MCF-7 cells. The inhibition of the MCF-7 cells' proliferation was also linked with apoptosis induction by flow-cytometry analysis. Additionally, the activation of apoptosis by both fractions was demonstrated by an increase in the ratio of Bax to Bcl-2, with an increase in the expression of caspase-7. Among the isolated compounds, glutinol (1) showed potent activity against the MCF-7 cell line, with an IC50 value of 9.83 µg/mL. Our findings suggest that E. saudiarabica has apoptosis-inducing effects and shows promise as a potential source of new chemotherapeutic drugs.

Elderberry Extracts: Characterization of the Polyphenolic Chemical Composition, Quality Consistency, Safety, Adulteration, and Attenuation of Oxidative Stress- and Inflammation-Induced Health Disorders.

Elderberry is highly reputed for its health-improving effects. Multiple pieces of evidence indicate that the consumption of berries is linked to enhancing human health and preventing or delaying the onset of chronic medical conditions. Compared with other fruit, elderberry is a very rich source of anthocyanins (approximately 80% of the polyphenol content). These polyphenols are the principals that essentially contribute to the high antioxidant and anti-inflammatory capacities and the health benefits of elderberry fruit extract. These health effects include attenuation of cardiovascular, neurodegenerative, and inflammatory disorders, as well as anti-diabetic, anticancer, antiviral, and immuno-stimulatory effects. Sales of elderberry supplements skyrocketed to $320 million over the year 2020, according to an American Botanical Council (ABC) report, which is attributable to the purported immune-enhancing effects of elderberry. In the current review, the chemical composition of the polyphenolic content of the European elderberry (Sambucus nigra) and the American elderberry (Sambucus canadensis), as well as the analytical techniques employed to analyze, characterize, and ascertain the chemical consistency will be addressed. Further, the factors that influence the consistency of the polyphenolic chemical composition, and hence, the consistency of the health benefits of elderberry extracts will be presented. Additionally, adulteration and safety as factors contributing to consistency will be covered. The role of elderberry in enhancing human health alone with the pharmacological basis, the cellular pathways, and the molecular mechanisms underlying the observed health benefits of elderberry fruit extracts will be also reviewed.

Eupatorin 3'-O-glucopyranoside, a trimethoxyflavonoid glucoside from the aerial parts of Salvia mellifera.

Salvia mellifera, native to California, Baja California, and Mexico, is a medicinal herb traditionally used to relieve pain, body aches, including chronic pain. A detailed phytochemical investigation of aerial parts of S. mellifera was accomplished to find species-specific markers and to differentiate the closely related, often (un)intentionally substituted with S. apiana. A total of 22 metabolites, including flavonoids (1-14), triterpenoids (15-18), diterpenoids (19-21), and phenylpropanoid (22), were isolated and characterized thoroughly. Among the isolates, eupatorin 3'-O-glucopyranoside (1) was identified as undescribed phytochemical and detailed structure elucidation was achieved through extensive NMR and mass spectral data analysis.

Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents.

The dried roots and rhizomes of Glycyrrhiza species (G. glabra, G. uralensis and G. inflata), commonly known as licorice, have long been used in traditional medicine. In addition, two other species, G. echinata and G. lepidota are also considered "licorice" in select markets. Currently, licorice is an integral part of several botanical drugs and dietary supplements. To probe the botanicals' safety, herb-drug interaction potential of the hydroethanolic extracts of five Glycyrrhiza species and their key constituents was investigated by determining their effects on pregnane X receptor, aryl hydrocarbon receptor, two major cytochrome P450 isoforms (CYP3A4 and CYP1A2), and the metabolic clearance of antiviral drugs. All extracts enhanced transcriptional activity of PXR and AhR (>2-fold) and increased the enzyme activity of CYP3A4 and CYP1A2. The highest increase in CYP3A4 was seen with G. echinata (4-fold), and the highest increase in CYP1A2 was seen with G. uralensis (18-fold) and G. inflata (16-fold). Among the constituents, glabridin, licoisoflavone A, glyasperin C, and glycycoumarin activated PXR and AhR, glabridin being the most effective (6- and 27-fold increase, respectively). Licoisoflavone A, glyasperin C, and glycycoumarin increased CYP3A4 activity while glabridin, glyasperin C, glycycoumarin, and formononetin increased CYP1A2 activity (>2-fold). The metabolism of antiretroviral drugs (rilpivirine and dolutegravir) was increased by G. uralensis (2.0 and 2.5-fold) and its marker compound glycycoumarin (2.3 and 1.6-fold). The metabolism of dolutegravir was also increased by G. glabra (2.8-fold) but not by its marker compound, glabridin. These results suggest that licorice and its phytochemicals could affect the metabolism and clearance of certain drugs that are substrates of CYP3A4 and CYP1A2.Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2050875 .

Strategy for the quality control of herbal preparations made of Sarcocephalus latifolius: Development and validation of a UHPLC-PDA method for quantification of angustoline and strictosamide and chemical profiling using LC-QToF.

INTRODUCTION: Sarcocephalus latifolius is one of the most used plants in West African traditional medicine to treat malaria. OBJECTIVE: The aim is to establish a strategy to control the quality of herbal preparations made from S. latifolius. METHOD: A UHPLC-PDA method was developed for the determination and quantification of the two main bioactive compounds (angustoline and strictosamide) in various parts of the plant. Additionally, an LC-QToF with electrospray ionization method is described for the identification and confirmation of compounds in samples of different parts of the plant. RESULTS: With the UHPLC-PDA method, separation was achieved within 5 min using a C18 column stationary phase at a temperature of 45°C and a gradient system with a mobile phase of water and acetonitrile, both containing 0.1% formic acid. The method was validated for linearity, accuracy, precision (repeatability and intermediate precision), limit of detection (LOD), and limit of quantification (LOQ). The LOD and LOQ of angustoline were found to be 0.3 and 0.8 µg/ml, respectively, and those of strictosamide were found to be 0.1 and 0.3 µg/ml, respectively. Using the LC-QToF method, 90 secondary metabolites, including four isolated compounds from the plant's roots, were identified from leaf, bark, and root samples of S. latifolius. CONCLUSION: This work is the first to propose a strategy to control the quality of herbal preparations made from S. latifolius. The developed method allows the quantification of the main bioactive compounds and the established chemical profile allows to distinguish the plant from any other species.

Metabolite variation and discrimination of five licorice (Glycyrrhiza) species: HPTLC and NMR explorations.

The roots and rhizomes of several Glycyrrhiza species are widely used as sweetening and flavoring agents in food, as well as important ingredients in formulations of traditional medicines. Five Glycyrrhiza species, G. uralensis, G. glabra, G. inflata, G. echinata, and G. lepidota, often share the name "licorice roots" in the botanicals' marketplace. Unfortunately, misidentification/mislabeling is very common due to their similarities in morpho-anatomical features. Significant metabolite alterations among the different Glycyrrhiza species and their hybrids have been reported, suggesting that the biological activities could vary with the licorice roots or products derived from different species. Development of simple, effective methods for species identification and differentiation is of key importance. In this study, 78 licorice samples were investigated using HPTLC and NMR as analytical tools. Significant metabolite variations were observed between the five species. The species-specific fingerprint patterns for the five Glycyrrhiza species were determined with HPTLC and NMR; then applied to the sample identification and discrimination. The results obtained from these two orthogonal analytical methods agreed with each other. Furthermore, the NMR signals and the species-specific constituents that made significant contributions to the differentiation of the five Glycyrrhiza species were confirmed based on the multivariate analysis of the NMR spectral data. Using the established OPLS-DA models, the classification of hybrids was evaluated and confirmed. The developed methods, particularly the HPTLC method with its simplicity and low cost, could be used as a rapid and reliable approach for the authentication of licorice species and quality control of licorice raw material and products.

Phytochemical analysis of Artemisia kopetdaghensis: Sesquiterpene lactones with proapoptotic activity against prostate cancer cells.

Phytochemical investigation of the aerial parts of Artemisia kopetdaghensis resulted in the isolation and characterization of three undescribed eudesmane-type sesquiterpene lactones, persianolide A, 4-epi-persianolide A, and 3α,4-epoxypersianolide A, together with three previously described eudesmane-type sesquiterpene lactones, 11-epi-artapshin, 1ß,8α-dihydroxy-11α,13-dihydrobalchanin, and 1ß-hydroxy-11-epi-colartin. The abundantly obtained 11-epi-artapshin was oxidized to undescribed 11α,13-dihydroeudesma-12,6α-olide-1,8-dione and 8ß-hydroxy-11α,13-dihydroeudesma-12,6α-olide-1-one and acetylated to the undescribed 1,8-O-diacetyl-11α,13-dihydroeudesma-12,6α-olide. Structures were elucidated based on extensive spectral data analyses, including 1D and 2D NMR and HRESIMS. The absolute configuration was determined using calculated and experimental ECD spectral data. Compounds were subsequently subjected to the MTT assay to evaluate their cytotoxicity against prostate cancer cells (DU-145 and LNCaP). Related factors associated with the sequence of apoptosis were tested by ELISA, western blotting, and biochemical assay. Results suggested that 11-epi-artapshin hinders the growth of DU-145 cells through mitochondria-mediated apoptosis initiated by stimulation of ROS build-up, ΔΨm depletion, regulation of the Bax/Bcl-2 ratio, and activation of caspase 3, respectively.

Simultaneous determination and characterization of flavonoids, sesquiterpene lactone, and other phenolics from Centaurea benedicta and dietary supplements using UHPLC-PDA-MS and LC-DAD-QToF.

Simultaneous identification and quantification of phenolic acid (chlorogenic acid), sesquiterpene lactone (cnicin), lignan (arctiin), and flavonoids (bracteoside, 6-methoxybracteoside, isokaempferide, and viscosine) in mixed parts of Centaurea benedicta (Syn. Cnicus benedictus) were performed for the first time. The liquid chromatography method showed an adequate performance for the separation of seven compounds. The method was validated for linearity (0.5-100 µg/mL), precision, accuracy, limit of detection (LOD), and limit of quantification (LOQ) as well as robustness. Cnicin and arctiin were detected at concentrations as low as 0.25 µg/mL. Remaining flavonoids and chlorogenic acid were detected at 0.025 µg/mL. The method demonstrated good performance in terms of intra- and inter-day precision (0.1-3.4%), accuracy (98.0-105.0%), lower and upper limits of quantification for all compounds. Analysis of various samples showed considerable variation of 0.9-10.3 mg/g for the marker compound, cnicin. Twenty-one dietary supplements, claiming to contain C. benedictus extract, were analyzed for authenticity. Thirteen (62%) of 21 products showed the presence of all analyzed compounds and were confirmed to contain C. benedictus. A liquid chromatography-tandem mass spectrometry method coupled with electrospray ionization (ESI) is described for the identification of compounds in plant samples. This method involved the use of protonated, deprotonated, and adduct ions for compounds in positive and negative ion modes with extractive ion chromatogram (EIC). The application of liquid chromatography-quadrupole time of flight mass spectrometry (LC-QToF) provided useful information to characterize sixty-four compounds. The developed methods were also applicable for quality assessment of raw materials and dietary supplements containing C. benedictus.

Probing PXR activation and modulation of CYP3A4 by Tinospora crispa and Tinospora sinensis.

ETHNOPHARMACOLOGICAL RELEVANCE: The two Tinospora species, T. crispa and T. sinensis, native to Southeast Asia, are integral components of various traditional preparations with structure-function claims to treat various disorders, including diabetes and inflammation. AIM OF THE STUDY: To assure the safety of the botanicals finished products, herb-drug interaction potential of T. crispa and T. sinensis was investigated by testing their extracts and compounds for in vitro activation of the pregnane X-receptor (PXR) and the modulation of CYP3A4 isozyme, selectively. MATERIALS AND METHODS: A total of sixteen fully characterized phytochemicals from T. crispa and T. sinensis were evaluated for PXR activation by luciferase reporter gene assay. CYP3A4 inhibition studies were carried out for eleven compounds. In addition, docking studies were performed to elucidate the possible binding modes to the PXR by the compounds using computational methods. RESULTS: Significant activation of PXR (2-fold) was observed for both extracts and non-polar fractions of T. crispa. Among the pure compounds, columbin showed highest activation of PXR (3-fold), which was comparable with the positive control, rifampicin. Vital interactions were predicted with docking simulation of PXR-columbin complex with critical amino acid residues (Trp-299) that are known for the activation of PXR. The methanolic extracts of T. crispa and T. sinensis also showed considerable CYP3A4 inhibition. CONCLUSION: T. crispa and T. sinensis, both demonstrated the potential to mediate herb-drug interaction through PXR activation and inhibition of CYP3A4 isozyme. Moreover, the elucidation of the potential to induce herb-drug interaction, by the phytochemicals of these Tinospora plants, thereby supports the need for further investigation to establish the clinical relevancy of these constituents for possible adverse interactions with pharmaceutical drugs.

Licochalcone L, an undescribed retrochalcone from Glycyrrhiza inflata roots.

Glycyrrhiza inflata Batalin is among the three glycyrrhizin producing Glycyrrhiza species and can be distinguished from other species with regard to its retrochalcone contents. Seven retrochalcones, echinatin and licochalcones A, C, D, E, K, and L were isolated and characterized from the chloroform extract of G. inflata roots. Among the isolates, licochalcone L was found to be previously undescribed. Structure elucidation of these specialised metabolites was achieved through NMR and mass spectroscopic data analyses.

Undescribed C-Glycosylflavones from Corn Silk and Potential Anti-inflammatory Activity Evaluation of Isolates.

Phytochemical investigation of corn silk resulted in isolation and characterization of four flavone C-glycosides, chrysoeriol 6-C-ß-oliopyranosyl-7-O-ß-D-glucopyranoside (1: ), 3'-methoxycassiaoccidentalin A (2: ), chrysoeriol 6-C-ß-boivinopyranosyl-7-O-ß-D-glucopyranoside (3: ), and ax-4″-OH-3'-methoxymaysin (4: ), a triterpenoid, friedelin (5: ), two sterols, (22E)-5α,8α-epidioxyergosta-6,22-dien-3ß-ol (6: ) and 6ß-hydroxystigmasta-4,22-diene-3-one (7: ), and a mixture of ß-sitosterol and stigmasterol. Compounds 1: and 2: were previously undescribed. Structure elucidation of the isolated compounds was attained using spectral data including 1D and 2D NMR and HRESIMS. Compounds1, 2, 5: , and 6: inhibited iNOS activity in LPS-induced macrophages and decreased nitrite levels by 68.64 ± 4.46, 65.67 ± 6.47, 88.50 ± 0.50, and 94.00 ± 4.00%, respectively, at 50 µM. Compound 5: also showed inhibition of NF-κB (51.00 ± 1.50%). Compounds 1: and 2: induced NAG-1 activity in chondrocytes by 1.80 ± 0.05 and 2.00 ± 0.13 fold, respectively. The extract of corn silk, however, did not exhibit inhibition of iNOS or NF-κB but induced NAG-1 by 1.80 ± 0.51 fold.

Phenoxychromone and 4-hydroxyisoflavans from the roots of Glycyrrhiza uralensis.

In an attempt to find species specific markers, a phenoxychromone (1) and eight isoflavonoids including six isoflavans (2-7) and two isoflavanones (8 and 9) were isolated from the root of Glycyrrhiza uralensis. Among the isolated phenolic compounds, glycyurelone (1), glycyurelvanins A and B (2 and 3) were found to be undescribed while others, (-)-vestitol (4), conferol A (5), glyasperin C (6), glyasperin D (7), (-)-licoisoflavanone (8), and (-)-3'-(γ,γ-dimethylallyl)kievitone (9) were previously reported. All compounds except 4 and 5 were prenylated and majority of these possess isoflavan scaffold with highly conserved stereo specificity at C-3 center. Structure elucidation was mainly based on extensive NMR, ECD and mass spectral data analysis.

Benzoylcyclopropane Derivatives from Hypoxis hemerocallidea Corms.

Two monobenzoylcyclopropane (hypoxhemerol A (1: ) and hypoxhemeroloside G (2: )) and three dibenzoylcyclopropane (hypoxhemerol B (3: ), hypoxhemeroloside H (4: ), and hypoxhemeroloside I (5: )) derivatives were isolated from the hydro-alcoholic extract of Hypoxis hemerocallidea corms. This is the first instance where benzoylcyclopropane analogs were isolated from any natural source. Structure elucidation was mainly based on 1D- and 2D-NMR and HRESIMS data. The absolute configuration (2R, 4R) of 1: was determined via NOESY NMR and experimental and calculated ECD data analyses. Compounds 1: -5: and 11 recently reported metabolites (hypoxoside, obtuside A, interjectin, acuminoside, curcapicycloside, and hypoxhemerolosides A - F) were screened for in vitro antimicrobial activity against various bacterial and fungal strains. Curcapicycloside and acuminoside exhibited antibacterial activity against Escherichia coli with 78 and 79% inhibition at 20 µg/mL, respectively. Hypoxhemeroloside A showed mild antifungal activity against Cryptococcus neoformans with 63% inhibition at 20 µg/mL.

Bulbine natalensis (currently Bulbine latifolia) and select bulbine knipholones modulate the activity of AhR, CYP1A2, CYP2B6, and P-gp.

Bulbine natalensis, an emerging medicinal herb on the global market with androgenic properties, is often formulated in dietary supplements that promote perceived sexual enhancement. However, to date, comprehensive safety studies of B. natalensis are lacking, particularly those related to its herb-drug interaction potential. The purpose of this study was to assess the inductive and inhibitory effects of extracts and pure compounds of B. natalensis on human cytochrome P-450 isozymes in vitro. Our findings demonstrated that both water and methanolic extracts of B. natalensis as well as knipholone, bulbine-knipholone, and 6'-O-methylknipholone dose-dependently increased mRNA expression encoded by CYP2B6, CYP1A2, and ABCB1 genes. Functional analyses showed that water (60 to 2.20 µg/mL) and methanolic (30 to 3.75 µg/mL) extracts and knipholones (10 to 0.33 µM) increased CYP2B6 and CYP1A2 activity in a dose-dependent manner. Additionally, water extract (60 µg/mL), methanolic extract (30 µg/mL), and knipholone (10 µM) caused activation of the aryl hydrocarbon receptor up to 11.1 ± 0.7, 8.9 ± 0.6, and 7.1 ± 2.0-fold, respectively. Furthermore, inhibition studies revealed that methanolic extract attenuated the activity of metabolically active CYP1A2 (IC50, 22.6 ± 0.4 µg/mL) and CYP2B6 (IC50, 34.2 ± 6.6 µg/mL) proteins, whereas water extracts had no inhibitory effect on either isoform. These findings suggest that chronic consumption of B. natalensis may affect normal homeostasis of select CYPs with subsequent risks for HDIs when concomitantly ingested with conventional medications that are substrates of CYP2B6 and CYP1A2. However, more in-depth translational studies are required to validate our current findings and their clinical relevance.