Terpenoids and steroids from aerial parts of Achillea alpina L. as PTP1B inhibitors: kinetic analysis and molecular docking studies.

Achillea alpina L. (Alpine yarrow) is a noteworthy herb in the genus Achillea with many uses in vegetables and traditionally used to treat stomach disorders. In our continuous research on the chemical constituents and biological activities of medicinal plants, ten previously undescribed terpenoids including eight eudesmane-type sesquiterpenes (1‒8), one nor-eudesmane-type sesquiterpene (9), one cyclo-geraniol derivative (10), and twenty-one known compounds were isolated and structurally elucidated from the aerial parts of A. alpina. Structures and absolute configurations of the undescribed terpenoids were identified using comprehensive spectroscopic analysis (NMR, HRESI-MS, and CD data) and computational methods (ECD and NMR calculation). Enzyme inhibitory assays showed that the isolated sesquiterpene (19), triterpene (22), and sterol (26) were protein tyrosine phosphatase 1B (PTP1B) inhibitors with IC50 values ranging from 14.87 to 23.09 µM in comparison with positive control - ursolic acid, showing IC50 value of 5.93 ± 0.16 µM. Further enzyme kinetics and molecular docking studies were performed to provide valuable insights into their mechanism of action.

Therapeutic Potential of Terpenoids in Cancer Treatment: Targeting Mitochondrial Pathways.

BACKGROUND: In recent decades, natural compounds have been considered a significant source of new antitumor medicines due to their unique advantages. Several in vitro and in vivo studies have focused on the effect of terpenoids on apoptosis mediated by mitochondria in malignant cells. RECENT FINDINGS: In this review article, we focused on six extensively studied terpenoids, including sesquiterpenes (dihydroartemisinin and parthenolide), diterpenes (oridonin and triptolide), and triterpenes (betulinic acid and oleanolic acid), and their efficacy in targeting mitochondria to induce cell death. Terpenoid-induced mitochondria-related cell death includes apoptosis, pyroptosis, necroptosis, ferroptosis, autophagy, and necrosis caused by mitochondrial permeability transition. Apoptosis and autophagy interact in meaningful ways. In addition, in view of several disadvantages of terpenoids, such as low stability and bioavailability, advances in research on combination chemotherapy and chemical modification were surveyed. CONCLUSION: This article deepens our understanding of the association between terpenoids and mitochondrial cell death, presenting a hypothetical basis for the use of terpenoids in anticancer management.

Recent Advances in Naturally Occurring [4+2] Type Terpenoid Dimers Assembled through Unmatched-electron-demand Cycloaddition.

Terpenoid dimers of the [4+2] type, which are naturally occurring compounds biosynthetically derived from the [4+2] cycloaddition of two synthons, have garnered considerable attention due to their complex molecular structures, diverse biological activities, and intriguing biosynthetic pathways. We have previously summarized the advancements in three types of [4+2] terpenoid dimers. In this review, we will focus on the lesser-explored class of [4+2] terpenoid dimers which assembled from two electron-deficient synthons via the unmatched-electron-demand Diels-Alder reaction  (UMEDDA). We will summarize their sources, biological activities, proposed biosynthesis, and chemical syntheses. Finally, a summary and outlook for this fascinating class of compounds will be presented.

Eco-friendly solvent-based liquid-liquid extraction of phenolic acids from winery wastewater streams.

This study proposes liquid-liquid extraction (LLE) for the recovery of phenolic acids from winery wastewater replacing common volatile organic compounds (VOCs) with environmentally friendly solvents. On one hand, terpenes (α-pinene and p-cymene) and terpenoids (eucalyptol and linalool) were selected as green solvents and compared to common VOCs (ethyl acetate or 1-butanol). On the other hand, gallic acid (GA), vanillic acid (VA), syringic acid (SA) and caffeic acid (CA) were selected as phenolic acids to be recovered. The extraction performance was evaluated under different operation conditions: solvent-to-feed ratio, initial concentration of phenolic acids and temperature. This work also evaluated the back-extraction whole process global recovery and solvent regeneration, by means of aqueous NaOH solution. Eucalyptol has shown the highest overall global extraction performance (21.07 % for GA, 93.21 % for VA, 78.79 % for SA, and 80.57 % for CA) and lower water solubility compared to the best performing VOC solvent (1-butanol). Therefore, eucalyptol can be a potential eco-friendly solvent to replace VOCs for sustainable phenolic acid recovery from winery wastewater. Finally, to ensure a clean water stream after the LLE, the traces of solvent were completely removed by electrooxidation with boron-doped diamond anode at a current density of 422.54 A/m2.

Lavandula angustifolia Herb from Ukraine: Comparative Chemical Profile and in†vitro Antioxidant Activity.

Lavandula L. genus plants have always been relevant as medicines for various purposes in food, medicine, pharmaceuticals, cosmetology and aromology. Ukraine is a new territory in the mass plant cultivation and lavender essential oil production. Therefore, the issue of integrated use of herbal raw materials and their intended use is still relevant. For the first time, ten samples of Lavendula angustifolia herb from 5 growing regions of Ukraine were studied for the composition and content of polyphenols and terpenoids using HPLC and HPTLC methods, respectively, to assess the prospects and quality of herbal raw materials. The results obtained showed that L. angustifolia herb has pronounced antioxidant activity due to the high content of phenolic compounds, namely hyperoside (5.665-11.629 mg/g), vanillic acid (5.986-11.196 mg/g), rosmarinic acid (0.211 to 1.488 mg/g), caffeic acid (0.369-3.835 mg/g), chlorogenic acid (0.239-4.619 mg/g), genistein-7-O-glucoside, as well as due to the presence of linalool and linalyl acetate, which was confirmed by qualitative analysis. The total antioxidant activity was the highest in samples from Lviv Botanical Garden (0.293 Trolox mg/mL), Kyiv OLawander (0.288 Trolox mg/mL), Kharkiv Bohodukhiv (0.270 Trolox mg/mL) which is due to the qualitative composition of phenolic compounds. At the same time, the most intense zones of terpenoids in lavender herb were noted for images from Kharkiv region Lebiazhe and Kitchenkivka villiges. Cluster analysis showed priority in the selection of marker compounds (vanillic acid, hyperoside, chlorogenic acid, rosmarinic acid) for lavender herb based on their quantitative content in the samples. In the future, lavender herb from Ukraine can be considered as a promising raw material with neuroprotective properties as part of its complex use, as research continues.

Exogenous stimulation of Tanacetum vulgare roots with pipecolic acid leads to tissue-specific responses in terpenoid composition.

Tanacetum vulgare L., tansy, is a perennial plant with highly variable terpenoid composition, with mono- and sesquiterpenoids being the most abundant. The high diversity of terpenoids plays an important role in mediating ecological interactions. However, the distribution of terpenoids in different tissues and inducibility of terpenoids in these tissues via biotic stress are poorly understood. We investigated changes in terpenoid profiles and concentrations in different organs following treatment of roots with pipecolic acid (Pip), a non-proteinogenic amino acid that triggers defence responses leading to induce systemic resistance (SAR) in plants. Tansy leaves and midribs contained mainly monoterpenoids, while coarse and fine roots contained mainly sesquiterpenoids. Rhizomes contained terpenoid profiles of both midribs and roots but also unique compounds. Treatment with Pip led to an increase in concentrations of mono- and sesquiterpenoids in all tissues except rhizomes. However, significantly more sesquiterpenoids was formed in root tissues in response to Pip treatment, compared to shoots. The metabolic atlas for terpenoids presented here shows that there is exceptionally strong differentiation of terpenoid patterns and terpenoid content in different tissues of tansy. This, together with differential inducibility by Pip, suggests that the chemical diversity of terpenoids may play an important role in tansy ecological interactions and defence against biotic stressors that feed on below- and aboveground organs.

The Chemical Ecology of Plant Natural Products.

Plants are excellent chemists with an impressive capability of biosynthesizing a large variety of natural products (also known as secondary or specialized metabolites) to resist various biotic and abiotic stresses. In this chapter, 989 plant natural products and their ecological functions in plant-herbivore, plant-microorganism, and plant-plant interactions are reviewed. These compounds include terpenoids, phenols, alkaloids, and other structural types. Terpenoids usually provide direct or indirect defense functions for plants, while phenolic compounds play important roles in regulating the interactions between plants and other organisms. Alkaloids are frequently toxic to herbivores and microorganisms, and can therefore also provide defense functions. The information presented should provide the basis for in-depth research of these plant natural products and their natural functions, and also for their further development and utilization.

Proteomic and metabolomic revealed the effect of shading treatment on cigar tobacco.

Shading or low light conditions are essential cultivation techniques for cigar wrapper tobacco leaves production, yet their impact on protein and metabolic regulatory networks is not well understood. In this study, we integrated proteomic and metabolomic analyses to uncover the potential molecular mechanisms affecting cigar tobacco leaves under shading treatment. Our findings include: (1) Identification of 780 significantly differentially expressed proteins (DEPs) in the cigar wrapper tobacco leaves, comprising 560 up-regulated and 220 down-regulated proteins, predominantly located in the chloroplast, cytoplasm, and nucleus, collectively accounting for 50.01%. (2) Discovery of 254 significantly differentially expressed metabolites (DEMs), including 148 up-regulated and 106 down-regulated metabolites. (3) KEGG pathway enrichment analysis revealed that the mevalonate (MVA) pathway within 'Terpenoid backbone biosynthesis' was inhibited, leading to a down-regulation of 'Sesquiterpenoid and triterpenoid biosynthesis'. Conversely, the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway was enhanced, resulting in an up-regulation of 'Monoterpenoid biosynthesis', 'Diterpenoid biosynthesis', and 'Carotenoid biosynthesis', thereby promoting the synthesis of terpenoids such as carotenoids and chlorophylls. Simultaneously, the Calvin cycle in 'Carbon fixation in photosynthetic organisms' was amplified, increasing photosynthetic efficiency. These results suggest that under low light conditions, cigar tobacco optimizes photosynthetic efficiency by reconfiguring its energy metabolism and terpenoid biosynthesis. This study contributes valuable insights into protein and metabolic analyses, paving the way for future functional studies on plant responses to low light.

Application of valencene and prospects for its production in engineered microorganisms.

Valencene, a sesquiterpene with the odor of sweet and fresh citrus, is widely used in the food, beverage, flavor and fragrance industry. Valencene is traditionally obtained from citrus fruits, which possess low concentrations of this compound. In the past decades, the great market demand for valencene has attracted considerable attention from researchers to develop novel microbial cell factories for more efficient and sustainable production modes. This review initially discusses the biosynthesis of valencene in plants, and summarizes the current knowledge of the key enzyme valencene synthase in detail. In particular, we highlight the heterologous production of valencene in different hosts including bacteria, fungi, microalgae and plants, and focus on describing the engineering strategies used to improve valencene production. Finally, we propose potential engineering directions aiming to further increase the production of valencene in microorganisms.

[Enzyme engineering in microbial biosynthesis of terpenoids: progress and perspectives].

Terpenoids, known for their structural and functional diversity, are highly valued, especially in food, cosmetics, and cleaning products. Microbial biosynthesis has emerged as a sustainable and environmentally friendly approach for the production of terpenoids. However, the natural enzymes involved in the synthesis of terpenoids have problems such as low activity, poor specificity, and insufficient stability, which limit the biosynthesis efficiency. Enzyme engineering plays a pivotal role in the microbial synthesis of terpenoids. By modifying the structures and functions of key enzymes, researchers have significantly improved the catalytic activity, specificity, and stability of enzymes related to terpenoid synthesis, providing strong support for the sustainable production of terpenoids. This article reviews the strategies for the modification of key enzymes in microbial synthesis of terpenoids, including improving enzyme activity and stability, changing specificity, and promoting mass transfer through multi-enzyme collaboration. Additionally, this article looks forward to the challenges and development directions of enzyme engineering in the microbial synthesis of terpenoids.

Exploring the therapeutic potential of cinnamoyl derivatives in attenuating inflammation in lipopolysaccharide-induced Caco-2 cells.

Aim: In gastrointestinal (GI) diseases, lipopolysaccharide (LPS) exacerbates gut-barrier dysfunction and inflammation. Cinnamoyl derivatives show potential in mitigating LPS-induced inflammation.Materials & methods: We assessed intestinal epithelial barrier function using Trans-epithelial electrical resistance values and measured inflammatory mediators through real-time PCR and ELISA in Caco-2 cells.Results: LPS treatment increased IL-6, IL-1ß, TNF-α, PGE2 and TRL4 expression in Caco-2 cells. Pre-treatment with DM1 (1 or 10 µM) effectively countered LPS-induced TLR4 overexpression and reduced IL-6, IL-1ß, TNF-α and PGE2 levels.Conclusion: DM1 holds promise in regulating inflammation and maintaining intestinal integrity by suppressing TLR4 and inflammatory mediators in Caco-2 cells. These findings suggest a potential therapeutic avenue for GI diseases.

[Box: see text].

Plant-Derived Terpenoids: A Plethora of Bioactive Compounds with Several Health Functions and Industrial Applications-A Comprehensive Overview.

Terpenoids are a large class of natural secondary plant metabolites which are highly diverse in structure, formed from isoprene units (C-5), associated with a wide range of biological properties, including antioxidant, antimicrobial, anti-inflammatory, antiallergic, anticancer, antimetastatic, antiangiogenesis, and apoptosis induction, and are considered for potential application in the food, cosmetics, pharmaceutical, and medical industries. In plants, terpenoids exert a variety of basic functions in growth and development. This review gives an overview, highlighting the current knowledge of terpenoids and recent advances in our understanding of the organization, regulation, and diversification of core and specialized terpenoid metabolic pathways and addressing the most important functions of volatile and non-volatile specialized terpenoid metabolites in plants. A comprehensive description of different aspects of plant-derived terpenoids as a sustainable source of bioactive compounds, their biosynthetic pathway, the several biological properties attributed to these secondary metabolites associated with health-promoting effects, and their potential industrial applications in several fields will be provided, and emerging and green extraction methods will also be discussed. In addition, future research perspectives within this framework will be highlighted. Literature selection was carried out using the National Library of Medicine, PubMed, and international reference data for the period from 2010 to 2024 using the keyword "terpenoids". A total of 177,633 published papers were found, of which 196 original and review papers were included in this review according to the criteria of their scientific reliability, their completeness, and their relevance to the theme considered.

FhMYB108 Regulates the Expression of Linalool Synthase Gene in Freesia hybrida and Arabidopsis.

Acting as the most abundant and widely distributed volatile secondary metabolites in plants, terpenoids play crucial roles in diverse physiological regulations and metabolic processes. Terpene synthases play a decisive role in determining the composition and diversity of terpenoids. Though the regulation of terpene synthases has been extensively investigated across various plant species, limited studies have focused on the upstream transcriptional regulation of terpene synthases. In this study, we have identified linalool as the predominant volatile compound that is released gradually from Freesia hybrida flowers throughout flower blooming. In the context of the transcriptome, a typical MYB transcription factor, FhMYB108, was screened based on homologous gene comparison. FhMYB108 is capable of regulating the expression of FhTPS1, and both their expression levels showed gradual increase during flower opening. Moreover, FhMYB108 exerts a stimulatory effect on the transcription of Arabidopsis thaliana AtTPS14, while no significant increase in AtTPS14 expression is observed upon the stabilization of FhMYB108 in A. thaliana. The highly expressed AtMYC2 in A. thaliana could interact with FhMYB108 to suppress the activation of AtTPS14 by FhMYB108. The present study not only elucidates the regulatory mechanism underlying linalool synthesis but also discovers the synergistic effect of MYB and bHLH transcription factors in governing the biosynthesis of volatile terpenoids.

Terpenoids from Marine Sources: A Promising Avenue for New Antimicrobial Drugs.

Currently, there is an urgent need for new antibacterial and antifungal agents to combat the growing challenge of antibiotic resistance. As the largest ecosystem on Earth, the marine ecosystem includes a vast array of microorganisms (primarily bacteria and fungi), plants, invertebrates, and vertebrates, making it a rich source of various antimicrobial compounds. Notably, terpenoids, known for their complex structures and diverse bioactivities, are a significant and promising group of compounds in the battle against bacterial and fungal infections. In the past five years, numerous antimicrobial terpenoids have been identified from marine organisms such as bacteria, fungi, algae, corals, sea cucumbers, and sponges. This review article provides a detailed overview of 141 terpenoids with antibacterial and/or antifungal properties derived from marine organisms between 2019 and 2024. Terpenoids, a diverse group of natural organic compounds derived from isoprene units, are systematically categorized based on their carbon skeleton structures. Comprehensive information is provided about their names, structures, biological sources, and the extent of their antibacterial and/or antifungal effectiveness. This review aims to facilitate the rapid identification and development of prospective antimicrobials in the pharmaceutical sector.

Retargeting of heterologous enzymes results in improved ß-carotene synthesis in Saccharomyces cerevisiae.

AIMS: Carotenoids are a class of hydrophobic substances that are important as food and feed colorants and as antioxidants. The pathway for ß-carotene synthesis has been expressed in various yeast species, albeit with rather low yields and titers. The inefficient conversion of phytoene to lycopene is often regarded as a bottleneck in the pathway. In this study, we aimed at the improvement of ß-carotene production in Saccharomyces cerevisiae by specifically engineering the enzymatic reactions producing and converting phytoene. METHODS AND RESULTS: We show that phytoene is stored in intracellular lipid droplets, whereas the enzyme responsible for its conversion, phytoene dehydrogenase, CrtI, is located at the endoplasmic reticulum, like the bifunctional enzyme CrtYB that catalyzes the reaction before and after CrtI. To improve the accessibility of phytoene for CrtI and to delay its storage in lipid droplets, we tested the relocation of CrtI and CrtYB to mitochondria. However, only the retargeting of CrtYB resulted in an improvement of the ß-carotene content, whereas the mitochondrial variant of CrtI was not functional. Surprisingly, a cytosolic variant of this enzyme, which we obtained through the elimination of its carboxy-terminal membrane anchor, caused an increase in ß-carotene accumulation. Overexpression of this CrtI variant in an optimized medium resulted in a strain with a ß-carotene content of 79 mg g-1 cell dry weight, corresponding to a 76-fold improvement over the starting strain. CONCLUSIONS: The retargeting of heterologously expressed pathway enzymes improves ß-carotene production in S. cerevisiae, implicating extensive inter-organellar transport phenomena of carotenoid precursors. In addition, strong overexpression of carotenoid biosynthetic enzymes and the optimization of cultivation conditions are required for high contents.

Genomics of Terpene Biosynthesis in Dictyoceratid Sponges (Porifera) - What Do We (Not) Know?

Sponges are recognized as promising sources for novel bioactive metabolites. Among them are terpenoid metabolites that constitute key biochemical defense mechanisms in several sponge taxa. Despite their significance, the genetic basis for terpenoid biosynthesis in sponges remains poorly understood. Dictyoceratida comprise demosponges well-known for their bioactive terpenoids. In this study, we explored the currently available genomic data for insights into the metabolic pathways of dictyoceratid terpenoids. We first identified prenyltransferase (PT) and terpene cyclase (TC) enzymes essential for the terpenoid biosynthetic processes in the terrestrial realm by analyzing available transcriptomic and genomic data of Dictyoceratida sponges and 10 other sponge species. All Dictyoceratida sponges displayed various PTs involved in either sesqui- or diterpene, steroid and carotenoid production. Additionally, it was possible to identify a potential candidate for a dictyoceratid sesterterpene PT. However, analogs of common terrestrial TCs were absent, suggesting the existence of a distinct or convergently evolved sponge-specific TC. Our study aims to contribute to the foundational understanding of terpene biosynthesis in sponges, unveiling the currently evident genetic components for terpenoid production in species not previously studied. Simultaneously, it aims to identify the known and unknown factors, as a starting point for biochemical and genetic investigations in sponge terpenoid production.

A Functional Switch Between Asperfumene and Fusicoccadiene Synthase and Entrance to Asperfumene Biosynthesis through a Vicinal Deprotonation-Reprotonation Process.

The diterpene synthase AfAS was identified from Aspergillus fumigatiaffinis. Its amino acid sequence and-according to a structural model-active site architecture are highly similar to those of the fusicocca-2,10(14)-diene synthase PaFS, but AfAS produces a structurally much more complex diterpene with a novel 6-5-5-5 tetracyclic skeleton called asperfumene. The cyclisation mechanism of AfAS was elucidated through isotopic labelling experiments and DFT calculations. The reaction cascade proceeds in its initial steps through similar intermediates as for the PaFS cascade, but then diverges through an unusual vicinal deprotonation-reprotonation process that triggers a skeletal rearrangement at the entrance to the steps leading to the unique asperfumene skeleton. The structural model revealed only one major difference between the active sites: The PaFS residue F65 is substituted by I65 in AfAS. Intriguingly, site-directed mutagenesis experiments with both diterpene synthases revealed that position 65 serves as a bidirectional functional switch for the biosynthesis of tetracyclic asperfumene versus structurally less complex diterpenes.

Naturally Derived Terpenoids Targeting the 3Dpol of Foot-and-Mouth Disease Virus: An Integrated In Silico and In Vitro Investigation.

Foot-and-mouth disease virus (FMDV) belongs to the Picornaviridae family and is an important pathogen affecting cloven-hoof livestock. However, neither effective vaccines covering all serotypes nor specific antivirals against FMDV infections are currently available. In this study, we employed virtual screening to screen for secondary metabolite terpenoids targeting the RNA-dependent RNA polymerase (RdRp), or 3Dpol, of FMDV. Subsequently, we identified the potential antiviral activity of the 32 top-ranked terpenoids, revealing that continentalic acid, dehydroabietic acid (abietic diterpenoids), brusatol, bruceine D, and bruceine E (tetracyclic triterpenoids) significantly reduced cytopathic effects and viral infection in the terpenoid-treated, FMDV-infected BHK-21 cells in a dose-dependent manner, with nanomolar to low micromolar levels. The FMDV minigenome assay demonstrated that brusatol and bruceine D, in particular, effectively blocked FMDV 3Dpol activity, exhibiting IC50 values in the range of 0.37-0.39 µM and surpassing the efficacy of the antiviral drug control, ribavirin. Continentalic acid and bruceine E exhibited moderate inhibition of FMDV 3Dpol. The predicted protein-ligand interaction confirmed that these potential terpenoids interacted with the main catalytic and bystander residues of FMDV 3Dpol. Additionally, brusatol and bruceine D exhibited additive effects when combined with ribavirin. In conclusion, terpenoids from natural resources show promise for the development of anti-FMD agents.

Isospongian Diterpenoids from the Leaves of Amomum tsao-ko Promote GLP-1 Secretion via Ca2+/CaMKII and PKA Pathways and Inhibit DPP-4 Enzyme.

Three uncommon isospongian diterpenoids including a new one, 3-epi-kravanhin A (2), were isolated from the leaves of Amomum tsao-ko. Compounds 2 and 3 dose-dependently promoted GLP-1 secretion on STC-1 cells with promotion ratios of 109.7% and 186.1% (60 µM). Mechanism study demonstrated that the GLP-1 stimulative effects of 2 and 3 were closely related with Ca2+/CaMKII and PKA pathways, but irrelevant to GPBAR1 and GPR119 receptors. Moreover, compound 1 showed moderate DPP-4 inhibitory activity with an IC50 value of 311.0 µM. Molecular docking verified the binding affinity of 1 with DPP-4 by hydrogen bonds between the γ-lactone carbonyl (C-15) and Arg61 residue. Bioinformatics study indicated that compound 1 exerted antidiabetic effects by improving inflammation, oxidative stress and insulin resistance. This study first disclosed the presence of isospongian diterpenoids in A. tsao-ko, which showed antidiabetic potency by promoting GLP-1 secretion and inhibiting DPP-4 activity.

Transformation of Terpenoids and Steroids Using Actinomycetes of the Genus Rhodococcus.

Terpenoids and steroids are secondary plant and animal metabolites and are widely used to produce highly effective pharmacologically significant compounds. One of the promising approaches to the transformation of these compounds to form bioactive metabolites is their transformation using microorganisms. Rhodococcus spp. are one of the most developed objects in biotechnology due to their exceptional metabolic capabilities and resistance to extreme environmental conditions. In this review, information on the processes of biotransformation of terpenoid and steroid compounds by actinomycetes of the genus Rhodococcus and their molecular genetic bases are most fully collected and analyzed for the first time. Examples of the use of both native whole-cell catalysts and mutant strains and purified enzyme systems for the production of derivatives of terpenoids and steroids are given.