Natural products as potential drug treatments for acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL), which was once considered one of the deadliest types of leukemia, has become a curable malignancy since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as clinical treatments. ATO, which has become the first-line therapeutic agent for APL, is derived from the natural mineral product arsenic, exemplifying an important role of natural products in the treatment of APL. Many other natural products, ranging from small-molecule compounds to herbal extracts, have also demonstrated great potential for the treatment and adjuvant therapy of APL. In this review, we summarize the natural products and representative components that have demonstrated biological activity for the treatment of APL. We also discuss future directions in better exploring their medicinal value, which may provide a reference for subsequent new drug development and combination therapy programs.

[Two new benzoyl-sesquiterpenes from Mesona chinensis].

Mesona chinensis is a common medicinal and edible plant in the Lingnan region of China, which has extensive pharmacological activity. However, the study of its chemical constituents is not sufficient. In this study, a variety of modern chromatographic separation techniques were used to isolate two compounds from 95% ethanol extract of the grass parts of M. chinensis. Their absolute configurations were determined by ultraviolet spectroscopy(UV), infrared spectroscopy(IR), high resolution mass spectrometry(HR-ESI-MS), 1D and 2D nuclear magnetic resonance(1D NMR and 2D NMR), and single-crystal X-ray diffraction(SC-XRD). Specifically, they were two new benzoyl-sesquiterpenes and named mesonanol A and mesonanol B, respectively. The results of the pharmacological activity evaluation showed that neither of the two new compounds showed obvious antiviral and anti-inflammatory activities.

Three rare anti-inflammatory sesquiterpene lactones from Magnolia grandiflora.

Four new sesquiterpene lactones (SLs) (1-4), along with a biosynthetically related SL (5), have been isolated from the leaves of Magnolia grandiflora. Magrandate A (1) is notable as the first C18 homogemarane type SL, featuring a unique 1,7-dioxaspiro[4.4]nonan-6-one core. Compounds 2 and 3, representing the first instances of chlorine-substituted gemarane-type SL analogs in natural products, were also identified. The structures of these isolates were elucidated through a combination of spectroscopic data analysis, electronic circular dichroism calculations, and X-ray single-crystal diffraction analysis. All isolates demonstrated anti-inflammatory activity in lipopolysaccharide-stimulated RAW264.7 cells. Notably, 3-5 showed a significant inhibitory effect on nitric oxide production, with IC50 values ranging from 0.79 to 4.73 µmol·L-1. Additionally, 4 and 5 exhibited moderate cytotoxic activities against three cancer cell lines, with IC50 values between 3.09 and 11.23 µmol·L-1.

Green nanotech paradigm for enhancing sesquiterpene lactone therapeutics in cancer.

In the field of cancer therapy, sesquiterpene lactones (SLs) derived from diverse Dicoma species demonstrate noteworthy bioactivity. However, the translation of their full therapeutic potential into clinical applications encounters significant challenges, primarily related to solubility, bioavailability, and precise drug targeting. Despite these obstacles, our comprehensive review introduces an innovative paradigm shift that integrates the inherent therapeutic properties of SLs with the principles of green nanotechnology. To overcome issues of solubility, bioavailability, and targeted drug delivery, eco-friendly strategies are proposed for synthesizing nanocarriers. Green nanotechnology has emerged as a focal point in addressing environmental and health concerns linked to conventional treatments. This progressive approach of green nanotechnology holds promise for the development of safe and sustainable nanomaterials, particularly in the field of drug delivery. This groundbreaking methodology signifies a pioneering advancement in the creation of novel and effective anticancer therapeutics. It holds substantial potential for transforming cancer treatment and advancing the landscape of natural product research.

New sesquiterpenoids with neuroprotective effects in vitro and in vivo from the Picrasma chinensis.

Three undescribed sesquiterpenes, designed as pichinenoid A-C (1-3), along with nine known ones (4-12) were isolated from the stems and leaves of Picrasma chinensis. The new isolates including their absolute configurations were elucidated based on extensive spectroscopic methods, single crystal X-ray diffraction, and electronic circular dichroism (ECD) experiments, as well as comparison with literature data. Structurally, compounds 1 and 2 are descending sesquiterpenes, while pichinenoid C (3) is a rare sesquiterpene bearing a 2-methylenebut-3-enoic acid moiety at the C-6 side chain. All the isolated compounds were tested for their neuroprotective effects against the H2O2-induced damage on human neuroblastoma SH-SY5Y cells, and most of them showed moderate neuroprotective activity. Especially, compounds 1, 3-5, and 7 showed a potent neuroprotective effect at 25 or 50 µM. Moreover, the neuroprotective effects of compounds 1 and 4 were tested on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Results of western blot and immunofluorescence indicated that compound 4 significantly counteract the toxicity of MPTP, and reversed the expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum (ST) of the mouse brain. Interestingly, western blot data suggested compound 4 also enhanced B-cell lymphoma-2 (Bcl-2) and heme oxygenase 1 (HO-1) expressions in the brain tissues from MPTP damaged mouse.

Plant Extracts and Phytochemicals from the Asteraceae Family with Antiviral Properties.

Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on a series of dichloromethane and methanolic extracts prepared from six Asteraceae species, including Acmella bellidioides, Campuloclinium macrocephalum, Grindelia pulchella, Grindelia chiloensis, Helenium radiatum, and Viguiera tuberosa, along with pure phytochemicals isolated from Asteraceae: mikanolide (1), eupatoriopicrin (2), eupahakonenin B (3), minimolide (4), estafietin (5), 2-oxo-8-deoxyligustrin (6), santhemoidin C (7), euparin (8), jaceidin (9), nepetin (10), jaceosidin (11), eryodictiol (12), eupatorin (13), and 5-demethylsinensetin (14). Results showed that the dichloromethane extracts of C. macrocephalum and H. radiatum and the methanolic extracts prepared from C. macrocephalum and G. pulchella were highly active and selective against DENV-2, affording EC50 values of 0.11, 0.15, 1.80, and 3.85 µg/mL, respectively, and SIs of 171.0, 18.8, >17.36, and 64.9, respectively. From the pool of phytochemicals tested, compounds 6, 7, and 8 stand out as the most active (EC50 = 3.7, 3.1, and 6.8 µM, respectively; SI = 5.9, 6.7, and >73.4, respectively). These results demonstrate that Asteraceae species and their chemical constituents represent valuable sources of new antiviral molecules.

Dauferulins A-L, daucane-type sesquiterpenes from the roots of Ferula communis: Their structures and biological activities.

Phytochemical study on the roots of a medicinal plant Ferula communis L. (Apiaceae) resulted in the isolation of 20 sesquiterpenes including 12 previously undescribed compounds, dauferulins A-L (1-12). The detailed spectroscopic analysis revealed 1-12 to be daucane-type sesquiterpenes with a p-methoxybenzoyloxy group at C-6. The absolute configurations of 1-12 were deduced by analysis of the ECD spectra. Dauferulins A-L (1-12), known sesquiterpenes (13-20), and analogues (14a-14l) derived from 6-O-p-methoxybenzoyl-10α-angeloyloxy-jeaschkeanadiol (14) were evaluated for their effects on AMPK phosphorylation in human hepatoma HepG2 cells as well as inhibitory activities against erastin-induced ferroptosis on human hepatoma Hep3B cells and IL-1ß production from LPS-treated murine microglial cells.

Discovery of sesquiterpene from Youngia japonica with antitumor effect.

Fourteen sesquiterpenes, including one undescribed sesquiterpene lactone, were isolated from Youngia japonica, and their structures were identified by NMR, HRESIMS, ECD and calculated ECD. Cytotoxic activities of all isolates against A549, HeLa, and 4 T1 cell lines were detected by CCK8 assay. Among them, 2 showed obvious cytotoxic activity against A549 cells. Subsequently, the production of ROS, and apoptosis of A549 cells treated with 2 were evaluated. The result showed that 2 distinctly increased the ROS level, and induced the apoptosis of A549 cells. Further anticancer mechanism studies showed that 2 increased the expression of cleaved caspase 3. Taken together, our results demonstrated that 2 might become potential leading compounds for the treatment of lung cancer.

Biocatalytic Regioselective O-acylation of Sesquiterpene Lactones from Chicory: A Pathway to Novel Ester Derivatives.

We report the first biocatalytic modification of sesquiterpene lactones (STLs) found in the chicory plants, specifically lactucin (Lc), 11ß,13-dihydrolactucin (DHLc), lactucopicrin (Lp), and 11ß,13-dihydrolactucopicrin (DHLp). The selective O-acylation of their primary alcohol group was carried out by the lipase B from Candida antarctica (CAL-B) using various aliphatic vinyl esters as acyl donors. Perillyl alcohol, a simpler monoterpenoid, served as a model to set up the desired O-acetylation reaction by comparing the use of acetic acid and vinyl acetate as acyl donors. Similar conditions were then applied to DHLc, where five novel ester chains were selectively introduced onto the primary alcohol group, with conversions going from >99 % (acetate and propionate) to 69 % (octanoate). The synthesis of the corresponding O-acetyl esters of Lc, Lp, and DHLp was also successfully achieved with near-quantitative conversion. Molecular docking simulations were then performed to elucidate the preferred enzyme-substrate binding modes in the acylation reactions with STLs, as well as to understand their interactions with crucial amino acid residues at the active site. Our methodology enables the selective O-acylation of the primary alcohol group in four different STLs, offering possibilities for synthesizing novel derivatives with significant potential applications in pharmaceuticals or as biocontrol agents.

(+)-Cedrol hemihydrate: a natural product derived from drying eastern red cedar (Juniperus virginiana) wood.

Cedrol-like compounds are of pharmacological interest due to their diverse range of medicinal effects and are used globally in traditional medicines and cosmetics. Many cedrol tautomers are known from molecular studies but few have been studied in crystalline form by X-ray diffraction. Acicular white crystals collected from the wood of eastern red cedar (Juniperus virginiana) are determined to be (+)-cedrol hemihydrate, namely, (1S,2R,5S,7R,8R)-2,6,6,8-tetramethyltricyclo[5.3.1.01,5]undecan-8-ol hemihydrate, C15H26O·0.5H2O, a novel packing of two unique cedrol molecules (Z' = 2) with a single water molecule [space group P212121; a = 6.1956 (1), b = 14.5363 (1), and c = 30.9294 (4) Å]. The hydrogen bonding forms a one-dimensional spiral chain running along the a axis, following the chirality of the cedrol molecule, through hydrogen-bonding interactions with a right-handed helical configuration in graph-set notation Δ-C33(6) > a > c > b. The crystal packing and symmetry are different from crystalline isocedrol due to the different hydrogen-bonding geometry.

Targeted screening of the synergistic components in Artemisia annua L. leading to enhanced antiplasmodial potency of artemisinin based on a "top down" PD-PK approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisinin (ART) showed enhanced antimalarial potency in the herb Artemisia annua L. (A. annua), from which ART is isolated. Increased absorption of ART with inhibited metabolism in the plant matrix is an underlying mechanism. Several synergistic components have been reported based on a "bottom-up" approach, i.e., traditional isolation followed by pharmacokinetic and/or pharmacodynamic evaluation. AIM OF THE STUDY: In this study, we employed a "top-down" approach based on in vivo antimalarial and pharmacokinetic studies to identify synergistic components in A. annua. MATERIALS AND METHODS: Two A. annua extracts in different chemical composition were obtained by extraction using ethyl acetate (EA) and petroleum ether (PE). The synergistic antimalarial activity of ART in two extracts was compared both in vitro (Plasmodium falciparum) and in vivo (murine Plasmodium yoelii). For the PD-PK correlation analysis, the pharmacokinetic profiles of ART and its major metabolite (ART-M) were investigated in healthy rats after a single oral administration of pure ART (20 mg/kg) or equivalent ART in each A. annua extract. A liquid chromatography-tandem high-resolution mass spectrometry (LC-HRMS)-based analytical strategy was then applied for efficient component classification and structural characterization of the differential components in the targeted extract with a higher antimalarial potency. Major components isolated from the targeted extract were then evaluated for their synergistic effect in the same proportion. RESULTS: Compared with pure ART (ED50, 5.6 mg/kg), ART showed enhanced antimalarial potency in two extracts in vivo (ED50 of EA, 2.9 mg/kg; ED50 of PE, 1.6 mg/kg), but not in vitro (IC50, 15.0-20.0 nM). A significant increase (1.7-fold) in ART absorption (AUC0-t) was found in rats after a single oral dose of equivalent ART in PE but not in EA; however, no significant change in the metabolic capability (AUCART-M/AUCART) was found for ART in either extract. The differential component analysis of the two extracts showed a higher composition of sesquiterpene compounds, especially component AB (3.0% in PE vs. 0.9% in EA) and component AA (14.1% in PE vs. 5.1% in EA). Two target sesquiterpenes were isolated and identified as arteannuin B (AB) and artemisinic acid (AA). The synergism between ART and AB/AA in the same proportion with PE extract (20:1.6:7.6, mg/kg) was verified by a pharmacokinetic study in rats. CONCLUSIONS: A "top-down" strategy based on PD-PK studies was successfully employed to identify synergistic components for ART in A. annua. Two sesquiterpene compounds (arteannuin B and artemisinic acid) could enhance the antimalarial potency of ART by increasing its absorption.

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.

Highly oxygenated guaiane-type sesquiterpene lactones from Artemisia sacrorum and their antihepatoma activity.

The ethanol and EtOAc extracts of Artemisia sacrorum exhibited inhibitory effect against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 65.5%, 28.1%, 84.6%, and 93.5%, 82.0%, 89.0% at 200 µg/mL. Twenty-three undescribed guaiane-type sesquiterpene lactones, artemisacrolides A‒W, were isolated from A. sacrorum under the guidance of antihepatoma activity. Their structures were elucidated by spectral data (HRESIMS, IR, UV, 1D and 2D NMR), ECD calculations, and a single-crystal X-ray diffraction. Artemisacrolides A‒U were guaiane-type sesquiterpene lactones possessing α-methylene-γ-lactone and containing acetoxyl groups at C-8, and artemisacrolides V and W represented the first report from the genus Artemisia with a 1,10-rearranged guaiane-type sesquiterpene lactone. Antihepatoma assay suggested that artemisacrolides A‒U demonstrated better inhibitory activity in Huh7 and SK-Hep-1 cells than those of HepG2 cells. Among them, nine compounds exhibited significant inhibitory activity against Huh7 cells with IC50 values of 8.2-14.3 µM, superior or equal to that of sorafenib; seven compounds demonstrated obvious activity against SK-Hep-1 cells with IC50 values of 13.5-19.2 µM, which were equivalent to that of sorafenib. Artemisacrolides B and E were the most active ones in three human hepatoma cell lines with IC50 values of 21.9, 8.2, 16.9 and 22.6, 9.0, 17.3 µM.

The Integration of the Metabolome and Transcriptome for Dendrobium nobile Lindl. in Response to Methyl Jasmonate.

Dendrobium nobile Lindl., as an endangered medicinal plant within the genus Dendrobium, is widely distributed in southwestern China and has important ecological and economic value. There are a variety of metabolites with pharmacological activity in D. nobile. The alkaloids and polysaccharides contained within D. nobile are very important active components, which mainly have antiviral, anti-tumor, and immunity improvement effects. However, the changes in the compounds and functional genes of D. nobile induced by methyl jasmonate (MeJA) are not clearly understood. In this study, the metabolome and transcriptome of D. nobile were analyzed after exposure to MeJA. A total of 377 differential metabolites were obtained through data analysis, of which 15 were related to polysaccharide pathways and 35 were related to terpenoids and alkaloids pathways. Additionally, the transcriptome sequencing results identified 3256 differentially expressed genes that were discovered in 11 groups. Compared with the control group, 1346 unigenes were differentially expressed in the samples treated with MeJA for 14 days (TF14). Moreover, the expression levels of differentially expressed genes were also significant at different growth and development stages. According to GO and KEGG annotations, 189 and 99 candidate genes were identified as being involved in terpenoid biosynthesis and polysaccharide biosynthesis, respectively. In addition, the co-expression analysis indicated that 238 and 313 transcription factors (TFs) may contribute to the regulation of terpenoid and polysaccharide biosynthesis, respectively. Through a heat map analysis, fourteen terpenoid synthetase genes, twenty-three cytochrome P450 oxidase genes, eight methyltransferase genes, and six aminotransferase genes were identified that may be related to dendrobine biosynthesis. Among them, one sesquiterpene synthase gene was found to be highly expressed after the treatment with MeJA and was positively correlated with the content of dendrobine. This study provides important and valuable metabolomics and transcriptomic information for the further understanding of D. nobile at the metabolic and molecular levels and provides candidate genes and possible intermediate compounds for the dendrobine biosynthesis pathway, which lays a certain foundation for further research on and application of Dendrobium.

Carotane sesquiterpenes from Peperomia pellucida and their anti-infective activities.

Owing to the challenges of antimicrobial resistance, investigations of new antibiotics from medicinal plants are continuously being conducted. Peperomia pellucida is a pantropical plant used in traditional medicine for the treatment of various disorders. From the ethanol extract of a whole P. pellucida plant, one previously undescribed carotane sesquiterpene (pellucarotine), one known carotane sesquiterpene (daucol), and one phenylpropanoid (dillapiol) were isolated and structurally elucidated. Their structures were determined based on 1D and 2D NMR, HR-ESI-Mass, experimental, and computational electronic circular dichroism spectroscopic data and compared with those reported in the literature. Antimicrobial assay results showed that pellucarotine had an anti-infective effect on Candida albicans with an MIC of 512 µg/mL.

Guaianolide-type sesquiterpene lactones from Achillea millefolium L. and their anti-inflammatory activity.

Seventeen undescribed guaianolide sesquiterpene lactones, millefoliumines A-Q, and seven known analogues were isolated from the whole plant of Achillea millefolium L. growing in Xinjiang, China. Their structures were elucidated based on the HRESIMS and NMR data analyses. The absolute configurations of millefoliumines A-Q were determined by single-crystal X-ray crystallography, ECD data analysis along with quantum-chemical ECD calculations. The anti-inflammatory effects of these compounds on the LPS-induced RAW264.7 cell model were evaluated. As a result, millefoliumine G exhibited potential inhibitory effects on the release of NO, the level of pro-inflammatory cytokines including TNF-α and IL-6. Above results indicated a potential of the guaianolides from A. millefolium in the anti-inflammatory drug development.

Improving Ginger's Bioactive Composition by Combining Innovative Drying and Extraction Technologies.

Ginger extracts (GEs) are antioxidant, antimicrobial, and anti-inflammatory. Their bioactivity can benefit foods and active packaging by extending shelf life, enhancing safety, and providing health benefits. Highly bioactive GEs are crucial to formulating potent active products and avoiding negative effects on their properties. Sesquiterpenes and phenolics are the main bioactives in ginger, but drying and extraction affect their composition. GEs are usually obtained from dry rhizomes; however, these operations have been studied independently. Therefore, a combined study of innovative drying and extraction technologies to evaluate their influence on extracts' composition will bring knowledge on how to increase the bioactivity of GEs. The effects of an emergent drying (vacuum microwave, VMD) followed by an emergent extraction (ultrasound, UAE, 20 or 80 °C) were investigated in this work. Microwave extraction (MAE) of fresh ginger was also studied. Convective oven drying and Soxhlet extraction were the references. Drying kinetics, powder color, extract composition, and antioxidant activity were studied. While MAE preserved the original composition profile, VMD combined with UAE (20 °C) produced extracts richer in phenolics (387.6 mg.GAE/g) and antioxidant activity (2100.7 mmol.Trolox/mL), with low impact in the sesquiterpenes. VMD generated shogaols by its high temperatures and facilitated extracting bioactives by destroying cellular structures and forming pores. UAE extracted these compounds selectively, released them from cell structures, and avoided losses caused by volatilization and thermal degradation. These findings have significant implications, as they provide an opportunity to obtain GE with tailored compositions that can enhance the formulation of food, active packaging, and pharmacological products.

The sesquiterpene lactone mix: A review of past, present and future aspects.

The sesquiterpene lactones (SLs) are secondary plant metabolites, which are widespread in the Compositae/Asteraceae plant family. The first SLs were detected more than 100 years ago, and allergic contact dermatitis from Compositae has been reported since the beginning of the 1900s, but it was not until the late 1960s and early 1970s that a collaboration between dermatologists, chemists and botanists led to the detection of SLs as the main allergens of Compositae plants. In the 1980s, the SL mix, consisting of equimolar amounts of alantolactone, costunolide and dehydrocostus lactone, was developed as a screening agent for Compositae sensitisation. Today, after inclusion of SL mix in the baseline series, the mean prevalence of reactions in Europe is around 1%, and in North America 0.8%. In countries outside Europe and North America, the prevalence ranges between 0% and 10.7%. The detection rate of SL mix is lower than that of some plant extracts, and ideally, SL mix should be supplemented with a mix of SLs from locally prevalent allergenic plants. The prevalence of positive reactions to SL mix suggests continued baseline testing in most European countries, North America, New Zealand, Australia and probably some Chinese centres.

Arnica montana L.: Doesn't Origin Matter?

Arnica montana L. (Asteraceae) has a long and successful tradition in Europe as herbal medicine. Arnica flowers (i.e., the flowerheads of Arnica montana) are monographed in the European Pharmacopoeia (Ph. Eur.), and a European Union herbal monograph exists, in which its use as traditional herbal medicine is recommended. According to this monograph, Arnica flowers (Arnicae flos Ph. Eur.) and preparations thereof may be used topically to treat blunt injuries and traumas, inflammations and rheumatic muscle and joint complaints. The main bioactive constituents are sesquiterpene lactones (STLs) of the helenanolide type. Among these, a variety of esters of helenalin and 11α,13-dihydrohelenalin with low-molecular-weight carboxylic acids, namely, acetic, isobutyric, methacrylic, methylbutyric as well as tiglic acid, represent the main constituents, in addition to small amounts of the unesterified parent STLs. A plethora of reports exist on the pharmacological activities of these STLs, and it appears unquestioned that they represent the main active principles responsible for the herbal drug's efficacy. It has been known for a long time, however, that considerable differences in the STL pattern occur between A. montana flowers from plants growing in middle or Eastern Europe with some originating from the Iberic peninsula. In the former, Helenalin esters usually predominate, whereas the latter contains almost exclusively 11α,13-Dihydrohelenalin derivatives. Differences in pharmacological potency, on the other hand, have been reported for the two subtypes of Arnica-STLs in various instances. At the same time, it has been previously proposed that one should distinguish between two subspecies of A. montana, subsp. montana occurring mainly in Central and Eastern Europe and subsp. atlantica in the southwestern range of the species distribution, i.e., on the Iberian Peninsula. The question hence arises whether or not the geographic origin of Arnica montana flowers is of any relevance for the medicinal use of the herbal drug and the pharmaceutical quality, efficacy and safety of its products and whether the chemical/pharmacological differences should not be recognized in pharmacopoeia monographs. The present review attempts to answer these questions based on a summary of the current state of botanical, phytochemical and pharmacological evidence.

Combination of microbial and chemical synthesis for the sustainable production of ß-elemene, a promising plant-extracted anticancer compound.

Beta-elemene, a class of sesquiterpene derived from the Chinese medicinal herb Curcuma wenyujin, is widely used in clinical medicine due to its broad-spectrum antitumor activity. However, the unsustainable plant extraction prompted the search for environmentally friendly strategies for ß-elemene production. In this study, we designed a Yarrowia lipolytica cell factory that can continuously produce germacrene A, which is further converted into ß-elemene with 100% yield through a Cope rearrangement reaction by shifting the temperature to 250°C. First, the productivity of four plant-derived germacrene A synthases was evaluated. After that, the metabolic flux of the precursor to germacrene A was maximized by optimizing the endogenous mevalonate pathway, inhibiting the competing squalene pathway, and expressing germacrene A synthase gene in multiple copies. Finally, the most promising strain achieved the highest ß-elemene titer reported to date with 5.08 g/L. This sustainable and green method has the potential for industrial ß-elemene production.