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Curcuma longae Rhizoma, commonly known as turmeric, is extensively utilized not only in Traditional Chinese Medicine (TCM) but also across various traditional medicine systems worldwide. It is renowned for its effectiveness in removing blood stasis, promoting blood circulation, and relieving pain. The primary bioactive metabolites of Curcuma longae Rhizoma--curcumin, β-elemene, curcumol, and curdione--have been extensively studied for their pharmacological benefits. These include anti-tumor properties, cardiovascular and cerebrovascular protection, immune regulation, liver protection, and their roles as analgesics, anti-inflammatories, antivirals, antibacterials, hypoglycemics, and antioxidants. This review critically examines the extensive body of research regarding the mechanisms of action of Curcuma longae Rhizoma, which engages multiple molecular targets and signaling pathways such as NF-κB, MAPKs, and PI3K/AKT. The core objective of this review is to assess how the main active metabolites of turmeric interact with these molecular systems to achieve therapeutic outcomes in various clinical settings. Furthermore, we discuss the challenges related to the bioavailability of these metabolites and explore potential methods to enhance their therapeutic effects. By doing so, this review aims to provide fresh insights into the optimization of Curcuma longae Rhizoma for broader clinical applications. [ABSTRACT FROM AUTHOR]

[Display omitted] β-Elemene (β-ELE), derived from Curcuma wenyujin , has anticancer effect on non-small cell lung cancer (NSCLC). However, the potential target and detail mechanism were still not clear. TFEB is the master regulator of lysosome biogenesis. Ferroptosis, a promising strategy for cancer therapy could be triggered via suppression on glutathione peroxidase 4 (GPX4). Weather TFEB-mediated lysosome degradation contributes to GPX4 decline and how β-ELE modulates on this process are not clear. To observe the action of β-ELE on TFEB, and the role of TFEB-mediated GPX4 degradation in β-ELE induced ferroptosis. Surface plasmon resonance (SPR) and molecular docking were applied to observe the binding affinity of β-ELE on TFEB. Activation of TFEB and lysosome were observed by immunofluorescence, western blot, flow cytometry and qPCR. Ferroptosis induced by β-ELE was observed via lipid ROS, a labile iron pool (LIP) assay and western blot. A549TFEB KO cells were established via CRISPR/Cas9. The regulation of TFEB on GPX4 and ferroptosis was observed in β-ELE treated A549WT and A549TFEB KO cells, which was further studied in orthotopic NOD/SCID mouse model. β-ELE can bind to TFEB, notably activate TFEB, lysosome and transcriptional increase on downstream gene GLA, MCOLN1, SLC26A11 involved in lysosome activity in EGFR wild-type NSCLC cells. β-ELE increased GPX4 ubiquitination and lysosomal localization, with the increase on lysosome degradation of GPX4. Furthermore, β-ELE induced ferroptosis, which could be promoted by TFEB overexpression or compromised by TFEB knockout. Genetic knockout or inactivation of TFEB compromised β-ELE induced lysosome degradation of GPX4, which was further demonstrated in orthotopic NSCLC NOD/SCID mice model. This study firstly demonstrated that TFEB promoted GPX4 lysosome degradation contributes to β-ELE induced ferroptosis in EGFR wild-type NSCLC, which gives a clue that TFEB mediated GPX4 degradation would be a novel strategy for ferroptosis induction and NSCLC therapy. [ABSTRACT FROM AUTHOR]

Sesquiterpenes and tetraterpenes are classes of plant-derived natural products with antineoplastic effects. While plant extraction of the sesquiterpene, germacrene A, and the tetraterpene, lycopene suffers supply chain deficits and poor yields, chemical synthesis has difficulties in separating stereoisomers. This review highlights cutting-edge developments in producing germacrene A and lycopene from microbial cell factories. We then summarize the antineoplastic properties of β-elemene (a thermal product from germacrene A), sesquiterpene lactones (metabolic products from germacrene A), and lycopene. We also elaborate on strategies to optimize microbial-based germacrene A and lycopene production. [ABSTRACT FROM AUTHOR]

Introduction: β-Elemene (β-ELE), derived from Curcuma wenyujin, has anticancer effect on non-small cell lung cancer (NSCLC). However, the potential target and detail mechanism were still not clear. TFEB is the master regulator of lysosome biogenesis. Ferroptosis, a promising strategy for cancer therapy could be triggered via suppression on glutathione peroxidase 4 (GPX4). Weather TFEB-mediated lysosome degradation contributes to GPX4 decline and how β-ELE modulates on this process are not clear. Objectives: To observe the action of β-ELE on TFEB, and the role of TFEB-mediated GPX4 degradation in β-ELE induced ferroptosis. Methods: Surface plasmon resonance (SPR) and molecular docking were applied to observe the binding affinity of β-ELE on TFEB. Activation of TFEB and lysosome were observed by immunofluorescence, western blot, flow cytometry and qPCR. Ferroptosis induced by β-ELE was observed via lipid ROS, a labile iron pool (LIP) assay and western blot. A549TFEB KO cells were established via CRISPR/Cas9. The regulation of TFEB on GPX4 and ferroptosis was observed in β-ELE treated A549WT and A549TFEB KO cells, which was further studied in orthotopic NOD/SCID mouse model. Results: β-ELE can bind to TFEB, notably activate TFEB, lysosome and transcriptional increase on downstream gene GLA, MCOLN1, SLC26A11 involved in lysosome activity in EGFR wild-type NSCLC cells. β-ELE increased GPX4 ubiquitination and lysosomal localization, with the increase on lysosome degradation of GPX4. Furthermore, β-ELE induced ferroptosis, which could be promoted by TFEB overexpression or compromised by TFEB knockout. Genetic knockout or inactivation of TFEB compromised β-ELE induced lysosome degradation of GPX4, which was further demonstrated in orthotopic NSCLC NOD/SCID mice model. Conclusion: This study firstly demonstrated that TFEB promoted GPX4 lysosome degradation contributes to β-ELE induced ferroptosis in EGFR wild-type NSCLC, which gives a clue that TFEB mediated GPX4 degradation would be a novel strategy for ferroptosis induction and NSCLC therapy.

Abstract Background Resident microglia- and peripheric macrophage-mediated neuroinflammation plays a predominant role in the occurrence and development of ischemic stroke. Microglia undergo polarization to M1/M2-like phenotype under stress stimulation, which mediates intracellular inflammatory response. β-elemene is a natural sesquiterpene and possesses potent anti-inflammatory activity. This study aimed to investigate the anti-inflammatory efficacy and mechanism of β-elemene in ischemic stroke from the perspective of balancing microglia M1/M2-like polarization. Methods The middle cerebral artery occlusion (MCAO) model and photothrombotic stroke model were established to explore the regulation effect of β-elemene on the cerebral ischemic injury. The LPS and IFN-γ stimulated BV-2 cells were used to demonstrate the anti-inflammatory effects and potential mechanism of β-elemene regulating M1/M2-like polarization in vitro. Results In C57BL/6 J mice subjected to MCAO model and photothrombotic stroke model, β-elemene attenuated neurological deficit, reduced the infarction volume and neuroinflammation, thus improving ischemic stroke injury. β-elemene promoted the phenotype transformation of microglia from M1-like to M2-like, which prevented neurons from oxygen and glucose deprivation/reoxygenation (OGD/R) injury by inhibiting inflammatory factor release, thereby reducing neuronal apoptosis. Mechanically, β-elemene prevented the activation of TLR4/NF-κΒ and MAPK signaling pathway and increased AKT/mTOR mediated-autophagy, thereby promoting M2-like polarization of microglia. Conclusions These results indicated that β-elemene improved cerebral ischemic injury and promoted the transformation of microglia phenotype from M1-like to M2-like, at least in part, through AKT/mTOR-mediated autophagy. This study demonstrated that β-elemene might serve as a promising drug for alleviating ischemic stroke injury.

Background: Resident microglia- and peripheric macrophage-mediated neuroinflammation plays a predominant role in the occurrence and development of ischemic stroke. Microglia undergo polarization to M1/M2-like phenotype under stress stimulation, which mediates intracellular inflammatory response. β-elemene is a natural sesquiterpene and possesses potent anti-inflammatory activity. This study aimed to investigate the anti-inflammatory efficacy and mechanism of β-elemene in ischemic stroke from the perspective of balancing microglia M1/M2-like polarization. Methods: The middle cerebral artery occlusion (MCAO) model and photothrombotic stroke model were established to explore the regulation effect of β-elemene on the cerebral ischemic injury. The LPS and IFN-γ stimulated BV-2 cells were used to demonstrate the anti-inflammatory effects and potential mechanism of β-elemene regulating M1/M2-like polarization in vitro. Results: In C57BL/6 J mice subjected to MCAO model and photothrombotic stroke model, β-elemene attenuated neurological deficit, reduced the infarction volume and neuroinflammation, thus improving ischemic stroke injury. β-elemene promoted the phenotype transformation of microglia from M1-like to M2-like, which prevented neurons from oxygen and glucose deprivation/reoxygenation (OGD/R) injury by inhibiting inflammatory factor release, thereby reducing neuronal apoptosis. Mechanically, β-elemene prevented the activation of TLR4/NF-κΒ and MAPK signaling pathway and increased AKT/mTOR mediated-autophagy, thereby promoting M2-like polarization of microglia. Conclusions: These results indicated that β-elemene improved cerebral ischemic injury and promoted the transformation of microglia phenotype from M1-like to M2-like, at least in part, through AKT/mTOR-mediated autophagy. This study demonstrated that β-elemene might serve as a promising drug for alleviating ischemic stroke injury. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic scars (HS) are a common disfiguring condition in daily clinical encounters which brings a lot of anxieties and concerns to patients, but the treatment options of HS are limited. Black cloth ointment (BCO), as a cosmetic ointment applicable to facial scars, has shown promising therapeutic effects for facial scarring. However, the molecular mechanisms underlying its therapeutic effects remain unclear. Material and methods: Network pharmacology was first applied to analyze the major active components of BCO and the related signaling pathways. Subsequently, rabbit ear scar model was successfully established to determine the pharmacological effects of BCO and its active component β‐elemene on HS. Finally, the molecular mechanism of BCO and β‐elemene was analyzed by Western blot. Results: Through the network pharmacology, it showed that β‐elemene was the main active ingredient of BCO, and it could significantly improve the pathological structure of HS and reduce collagen deposition. BCO and β‐elemene could increase the expression of ER stress‐related markers and promote the increase of apoptotic proteins in the Western blot experiment and induce the apoptosis of myofibroblasts. Conclusions: Our findings indicate that the material basis for the scar‐improving effects of the BCO is β‐elemene, and cellular apoptosis is the key mechanism through which the BCO and β‐elemene exert their effects. [ABSTRACT FROM AUTHOR]

Lung cancer is a leading cause of mortality worldwide, especially among Asian patients with non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Initially, first-generation EGFR tyrosine kinase inhibitors (TKIs) are commonly administered as the primary treatment option; however, encountering resistance to these medications poses a significant obstacle. Hence, it has become crucial to address initial resistance and ensure continued effectiveness. Recent research has focused on the role of long noncoding RNAs (lncRNAs) in tumor drug resistance, especially lncRNA H19. β-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between β-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether β-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and β-elemene on cell viability was evaluated using the cell counting kit-8 (CCK8) assay. Furthermore, western blotting and qRT-PCR analysis were employed to determine the expression levels of autophagy-related proteins and genes, respectively. The influence on cellular proliferation was gauged through a colony-formation assay, and apoptosis induction was quantified via flow cytometry. Additionally, the tumorigenic potential in vivo was assessed using a xenograft model in nude mice. The expression levels of LC3B, EGFR, and Rab7 proteins were examined through immunofluorescence. Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of β-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, β-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, β-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. β-elemene emerges as a promising auxiliary therapeutic for circumventing gefitinib resistance in NSCLC, potentially through the regulation of lncRNA H19-mediated autophagy. The participation of Rab7 in this dynamic unveils novel insights into the resistance mechanisms operative in lung cancer, paving the way for future therapeutic innovations. [ABSTRACT FROM AUTHOR]

β-elemene has been observed to exert inhibitory effects on a multitude of tumors, primarily through multiple pathways such as the inhibition of cancer cell proliferation and the induction of apoptosis. The present study is designed to elucidate the role and underlying mechanisms of β-elemene in the therapeutic intervention of non-small cell lung cancer (NSCLC). Both in vitro and in vivo experimental models corroborate the inhibitory potency of β-elemene on NSCLCs. Our findings indicate that β-elemene facilitates the maturation of miR-127-3p by inhibiting CBX8. Functioning as an upstream regulator of MAPK4, miR-127-3p deactivates the Akt/mTOR/p70S6K pathway by targeting MAPK4, thereby inducing autophagy in NSCLCs. Additionally, β-elemene augments the packaging of miR-127-3p into exosomes via SYNCRIP. Exosomal miR-127-3p further stimulates M1 polarization of macrophages by suppressing ZC3H4. Taken together, the detailed understanding of the mechanisms through which β-elemene induces autophagy in NSCLCs and facilitates M1 polarization of macrophages provides compelling scientific evidence supporting its potential utility in NSCLC treatment.

Cervical cancer is a leading cause of cancer-related mortality in females worldwide, necessitating urgent solutions for effective treatment. Paclitaxel (PTX), a natural diterpene alkaloid compound, has the ability to inhibit mitosis and induce programmed apoptosis in tumor cells. However, its toxicity and drug resistance limit its efficacy in certain cervical cancer patients. β-elemene (β-ELE) can reverse multidrug resistance by inhibiting ATP-binding cassette transporters, thereby enhancing chemotherapy drug retention. Therefore, we propose a combination therapy using PTX/β-ELE to improve chemotherapy sensitivity. To enhance targeted drug delivery, we developed M1-macrophage-membrane-coated nanoparticles (M1@PLGA/PTX/β-ELE) for co-delivery of PTX&β-ELE. Through both in vitro and in vivo cervical cancer models, we demonstrated that M1@PLGA/PTX/β-ELE effectively suppressed tumor progression and polarization of tumor-associated macrophages. Furthermore, H&E staining confirmed the high therapeutic biosafety of M1@PLGA/PTX/β-ELE as there was no significant damage observed in major organs throughout the entire therapeutic process. Overall, this study presents a targeted biomimetic nanoplatform and combinatorial strategy that synergistically enhances chemosensitivity in malignant tumors.

Main conclusion: The study demonstrated thatArtemisia pallensroots can be a source of terpene-rich essential oil and root-specific ApTPS1 forms germacrene A contributing to major root volatiles. Davana (Artemisia pallens Bess) is a valuable aromatic herb within the Asteraceae family, highly prized for its essential oil (EO) produced in the aerial parts. However, the root volatile composition, and the genes responsible for root volatiles have remained unexplored until now. Here, we show that A. pallens roots possess distinct oil bodies and yields ~ 0.05% of EO, which is primarily composed of sesquiterpenes β-elemene, neryl isovalerate, β-selinene, and α-selinene, and trace amounts of monoterpenes β-myrcene, D-limonene. This shows that, besides aerial parts, roots of davana can also be a source of unique EO. Moreover, we functionally characterized a terpene synthase (ApTPS1) that exhibited high in silico expression in the root transcriptome. The recombinant ApTPS1 showed the formation of β-elemene and germacrene A with E,E-farnesyl diphosphate (FPP) as a substrate. Detailed analysis of assay products revealed that β-elemene was the thermal rearrangement product of germacrene A. The functional expression of ApTPS1 in Saccharomyces cerevisiae confirmed the in vivo germacrene A synthase activity of ApTPS1. At the transcript level, ApTPS1 displayed predominant expression in roots, with significantly lower level of expression in other tissues. This expression pattern of ApTPS1 positively correlated with the tissue-specific accumulation level of germacrene A. Overall, these findings provide fundamental insights into the EO profile of davana roots, and the contribution of ApTPS1 in the formation of a major root volatile. [ABSTRACT FROM AUTHOR]

In China, β‐elemene, a sesquiterpene compound derived from Curcuma wenyujin, is clinically used to treat many human malignancies, including non‐small cell lung cancer (NSCLC). Nonetheless, the role of β‐elemene in regulating cisplatin sensitivity of NSCLC cells and the related mechanisms are not clear. This study was conducted to investigate the role of β‐elemene in sensitizing NSCLC cells to cisplatin. In this work, cisplatin‐resistant NSCLC cell lines were constructed. CCK‐8, colony formation, and flow cytometry assays were executed to examine cell viability, growth, and apoptosis. MiR‐17‐5p and STAT3 expression levels in cells were detected by qRT‐PCR. Western blot was executed to determine the expression levels of STAT3 and apoptosis‐related proteins (Bax and Bcl‐2) in the cells. Dual‐luciferase reporter gene experiments were performed to verify the targeting relationship between miR‐17‐5p and STAT3. Herein, we report that, β‐elemene inhibits the viability, and induces the apoptosis of cisplatin‐resistant NSCLC cells. Additionally, β‐elemene induces the upregulation miR‐17‐5p and downregulation of STAT3. STAT3 is validated to be a target of miR‐17‐5p in NSCLC cells. Additionally, the role of β‐elemene to repress the viability of cisplatin‐resistant NSCLC cells is partially counteracted by miR‐17‐5p inhibitor or STAT3 overexpression. In summary, our study suggests that β‐elemene enhances cisplatin sensitivity of NSCLC cells by modulating miR‐17‐5p/STAT3 axis, and it may be a choice for the complementary treatment of NSCLC patients. [ABSTRACT FROM AUTHOR]

Esophageal stricture caused by fibrosis is a serious complication after esophageal Endoscopic submucosal dissection (ESD). Myofibroblasts play a crucial role in esophageal fibrosis, so inhibiting activated myofibroblasts is a promising approach for treating esophageal fibrosis. β-Elemene, a natural product with anti-tumor and anti-fibrotic properties, has not been thoroughly examined in esophageal fibrosis. Additionally, fibroblast activation protein (FAP) and PTEN-PI3K/AKT signaling pathway are both notably linked to fibrotic diseases. Therefore, we investigated the potential mechanisms of β-elemene in esophageal fibrosis by treating primary human esophageal granulation fibroblasts (PHEGFs) with gradient concentrations of β-elemene. Our findings demonstrated that β-elemene inhibited the activity of PHEGFs in a dose-dependent manner, accompanied by downregulation of FAP, p-PI3K, and p-AKT protein expression, along with upregulation of p-PTEN protein expression. In addition, we substantiated the potential correlation between FAP and the PTEN-PI3K/AKT signaling pathway by establishing models of FAP overexpression and silencing. These results provide a new perspective on the potential mechanism of β-elemene in relieving esophageal fibrosis and offer novel therapeutic strategies for managing post-esophageal ESD stricture in clinical practice.

β-Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its scaffold. Systematic SAR studies led to the discovery of compounds 27f and 39f, which exhibited potent inhibitory activity against HDACs (HDAC1: IC50 = 22 and 9 nM; HDAC6: 8 and 14 nM, respectively). In cellular levels, 27f and 39f significantly inhibited cell proliferation of five tumour cell lines (IC50: 0.79 - 4.42 µM). Preliminary mechanistic studies indicated that 27f and 39f efficiently induced cell apoptosis. Unexpectedly, compound 39f could also stimulate cell cycle arrest in G1 phase. Further in vivo study in WSU-DLCL-2 xenografted mouse model validated the antitumor activities of 27f, without significant toxicity. The results suggest the therapeutic potential of these HDACs inhibitors in lymphoma and provide valuable insight and understanding for further structural optimisation around β-elemene scaffold. [ABSTRACT FROM AUTHOR]

Natural products are essential sources of antitumor drugs. One such molecule, β -elemene, is a potent antitumor compound extracted from Curcuma wenyujin. In the present investigation, a series of novel 13,14-disubstituted nitric oxide (NO)-donor β -elemene derivatives were designed, with β -elemene as the foundational compound, and subsequently synthesized to evaluate their therapeutic potential against leukemia. Notably, the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line, with a high NO release. In vivo studies indicated that compound 13d could effectively inhibit tumor growth, exhibiting no discernible toxic manifestations. Specifically, a significant tumor growth inhibition rate of 62.9% was observed in the K562 xenograft tumor mouse model. The accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia. [ABSTRACT FROM AUTHOR]

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Tumor‐associated macrophages (TAMs) play a critical role in the immunosuppressive solid tumor microenvironment (TME), yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significant challenge in translational immuno‐oncology. Here, we report an innovative nanodrug‐delivering‐drug (STNSP@ELE) strategy that leverages two‐dimensional (2D) stanene‐based nanosheets (STNSP) and β‐Elemene (ELE), a small‐molecule anticancer drug, to overcome TAM‐mediated immunosuppression and improve chemo‐immunotherapy. Our results demonstrate that both STNSP and ELE are capable of polarizing the tumor‐supportive M2‐like TAMs into a tumor‐suppressive M1‐like phenotype, which acts with the ELE chemotherapeutic to boost antitumor responses. In vivo mouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantly increasing the intratumoral ratio of M1/M2‐like TAMs, enhancing the population of CD4+ and CD8+ T lymphocytes and mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, thereby promoting a robust antitumor response. Our study not only demonstrates that the STNSP@ELE chemo‐immunotherapeutic nanoplatform has immune‐modulatory capabilities that can overcome TAM‐mediated immunosuppression in solid tumors, but also highlights the promise of this nanodrug‐delivering‐drug strategy in developing other nano‐immunotherapeutics and treating various types of immunosuppressive tumors. [ABSTRACT FROM AUTHOR]

β-Elemene (C15H24), a sesquiterpenoid compound isolated from the volatile oil of Curcuma wenyujin, has been proven to be effective for multiple cancers and is widely used in clinical treatment. Unfortunately, the β-elemene content in C. wenyujin is very low, which cannot meet market demands. Our previous research showed that methyl jasmonate (MeJA) induced the accumulation of β-elemene in C. wenyujin. However, the regulatory mechanism is unclear. In this study, 20 jasmonate ZIM-domain (JAZ) proteins in C. wenyujin were identified, which are the core regulatory factors of the JA signaling pathway. Then, the conservative domains, motifs composition, and evolutionary relationships of CwJAZs were analyzed comprehensively and systematically. The interaction analysis indicated that CwJAZs can form homodimers or heterodimers. Fifteen out of twenty CwJAZs were significantly induced via MeJA treatment. As the master switch of the JA signaling pathway, the CwMYC2-like protein has also been identified and demonstrated to interact with CwJAZ2/3/4/5/7/15/17/20. Further research found that the overexpression of the CwMYC2-like gene increased the accumulation of β-elemene in C. wenyujin leaves. Simultaneously, the expressions of HMGR, HMGS, DXS, DXR, MCT, HDS, HDR, and FPPS related to β-elemene biosynthesis were also up-regulated by the CwMYC2-like protein. These results indicate that CwJAZs and the CwMYC2-like protein respond to the JA signal to regulate the biosynthesis of β-elemene in C. wenyujin. [ABSTRACT FROM AUTHOR]

β‐elemene is one of the most commonly used antineoplastic drugs in cancer treatment. As a plant‐derived natural chemical, biologically engineering microorganisms to produce germacrene A to be converted to β‐elemene harbors great expectations since chemical synthesis and plant isolation methods come with their production deficiencies. In this study, we report the design of an Escherichia coli cell factory for the de novo production of germacrene A to be converted to β‐elemene from a simple carbon source. A series of systematic approaches of engineering the isoprenoid and central carbon pathways, translational and protein engineering of the sesquiterpene synthase, and exporter engineering yielded high‐efficient β‐elemene production. Specifically, deleting competing pathways in the central carbon pathway ensured the availability of acetyl‐coA, pyruvate, and glyceraldehyde‐3‐phosphate for the isoprenoid pathways. Adopting lycopene color as a high throughput screening method, an optimized NSY305N was obtained via error‐prone polymerase chain reaction mutagenesis. Further overexpression of key pathway enzymes, exporter genes, and translational engineering produced 1161.09 mg/L of β‐elemene in a shake flask. Finally, we detected the highest reported titer of 3.52 g/L of β‐elemene and 2.13 g/L germacrene A produced by an E. coli cell factory in a 4‐L fed‐batch fermentation. The systematic engineering reported here generally applies to microbial production of a broader range of chemicals. This illustrates that rewiring E. coli central metabolism is viable for producing acetyl‐coA‐derived and pyruvate‐derived molecules cost‐effectively. [ABSTRACT FROM AUTHOR]

Background: β-Elemene (IUPAC name: (1 S,2 S,4 R)−1-ethenyl-1-methyl-2,4-bis(prop-1-en-2-yl) cyclohexane), is a natural compound found in turmeric root. Studies have demonstrated its diverse biological functions, including its anti-tumor properties, which have been extensively investigated. However, these have not yet been reviewed. The aim of this review was to provide a comprehensive summary of β-elemene research, with respect to disease treatment. Methods: β-Elemene-related articles were found in PubMed, ScienceDirect, and Google Scholar databases to systematically summarize its structure, pharmacokinetics, metabolism, and pharmacological activity. We also searched the Traditional Chinese Medicine System Pharmacology database for therapeutic targets of β-elemene. We further combined these targets with the relevant literature for KEGG and GO analyses. Results: Studies on the molecular mechanisms underlying β-elemene activity indicate that it regulates multiple pathways, including STAT3, MAPKs, Cyclin-dependent kinase 1/cyclin B, Notch, PI3K/AKT, reactive oxygen species, METTL3, PTEN, p53, FAK, MMP, TGF-β/Smad signaling. Through these molecular pathways, β-elemene has been implicated in tumor cell proliferation, apoptosis, migration, and invasion and improving the immune microenvironment. Additionally, β-elemene increases chemotherapeutic drug sensitivity and reverses resistance by inhibiting DNA damage repair and regulating pathways including CTR1, pak1, ERK1/2, ABC transporter protein, Prx-1 and ERCC-1. Nonetheless, owing to its lipophilicity and low bioavailability, additional structural modifications could improve the efficacy of this drug. Conclusion: β-Elemene exhibits low toxicity with good safety, inhibiting various tumor types via diverse mechanisms in vivo and in vitro. When combined with chemotherapeutic drugs, it enhances efficacy, reduces toxicity, and improves tumor killing. Thus, β-elemene has vast potential for research and development.

Abstract β-Elemene, an active ingredient found in medicinal plants like turmeric and zedoary, is a sesquiterpene compound with antitumor activity against various cancers. However, its current mode of production through plant extraction suffers from low efficiency and limited natural resources. Recently, there has been an increased interest in establishing microbial cell factories to produce germacrene A, which can be converted to β-elemene by a one-step reaction in vitro. In this study, we constructed an engineered Pichia pastoris cell factory for producing germacrene A. We rerouted the fluxes towards germacrene A biosynthesis through the optimization of the linker sequences between germacrene A synthase (GAS) and farnesyl pyrophosphate synthase (ERG20), overexpression of important pathway genes (i.e., IDI1, tHMG1, and ACS), and multi-copy integration of related expression cassettes. In combination with medium optimization and bioprocess engineering, the final titer of germacrene A in a 1 L fermenter reached 1.9 g/L through fed-batch fermentation. This represents the first report on the production of germacrene A in P. pastoris and demonstrates its advantage in producing terpenoids and other value-added natural products. Graphical Abstract

Lung cancer is a leading cause of mortality worldwide, especially among Asian patients with non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Initially, first-generation EGFR tyrosine kinase inhibitors (TKIs) are commonly administered as the primary treatment option; however, encountering resistance to these medications poses a significant obstacle. Hence, it has become crucial to address initial resistance and ensure continued effectiveness. Recent research has focused on the role of long noncoding RNAs (lncRNAs) in tumor drug resistance, especially lncRNA H19. β-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between β-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether β-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and β-elemene on cell viability was evaluated using the cell counting kit-8 (CCK8) assay. Furthermore, western blotting and qRT-PCR analysis were employed to determine the expression levels of autophagy-related proteins and genes, respectively. The influence on cellular proliferation was gauged through a colony-formation assay, and apoptosis induction was quantified via flow cytometry. Additionally, the tumorigenic potential in vivo was assessed using a xenograft model in nude mice. The expression levels of LC3B, EGFR, and Rab7 proteins were examined through immunofluorescence. Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of β-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, β-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, β-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. β-elemene emerges as a promising auxiliary therapeutic for circumventing gefitinib resistance in NSCLC, potentially through the regulation of lncRNA H19-mediated autophagy. The participation of Rab7 in this dynamic unveils novel insights into the resistance mechanisms operative in lung cancer, paving the way for future therapeutic innovations.

Objective To explore the clinical effect of utrasound and bronchoscopy-guided iodine-125 ( I-125) radioactive seeds implantation combined with β-elemene in the treatment of advanced mediastinal lung carcinoma. Methods A total of 120 patients with advanced mediastinal lung carcinoma in Chongqing Traditional Chinese Medicine Hospital from September 2017 to January 2021 were enrolled and divided randomly into I-125 seeds group, β-elemene group and combination group (I-125 seeds + β-elemene) according to the treatment method (n=40, each) . The short-term clinical efficacy, serum tumor markers, distant metastasis and 1-year survival were compared among three groups . Results At 2, 4 and 6 months after treatment, the curative effects of combination group and I-125 seed group were significantly better than those in β-elemene group (P＜0.05) . Compared with those before treatment and in β-elemene group, the airway diameter, percentage predictive forced expiratory volume in first second (FEV1%) and 6-min walking distance (6MWD) increased, and the shortness of breath index decreased significantly in combination group and I-125 seed group at 2, 4 and 6 months after treatment (P＜0.05) . In combination group, the serum levels of carcinoembryonic antigen (CEA) , squamous cell carcinoma antigen (SCC) and cytokeratin 19 fragment (CYFRA 21-1) and tissue peptide antigen (TPA) were lower than those before treatment (P＜0.05) , and the maximum cross-sectional area of the lesions significantly reduced at 4 months after treatment (P＜0.01) . After 1 year follow-up, the survival rate in combination group (87.5%) was higher than that in I-125 seeds group (62.5%) and β-elemene group (52.5%) (P＜0.05) . Conclusion In the treatment of patients with advanced mediastinal lung carcinoma, ultrasound and bronchoscopy-guided I-125 radioactive seeds implantation combined with β-elemene is an effective, safe and feasible measure, with good short-term prognosis, which is superior to single I-125 radioactive seeds implantation and alone use of β-elemene. It has been confirmed that β-elemene has radiosensitization effect and synergistic anti-tumor effect when combined with I-125 radioactive seeds implantation.

β-Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its scaffold. Systematic SAR studies led to the discovery of compounds 27f and 39f, which exhibited potent inhibitory activity against HDACs (HDAC1: IC50 = 22 and 9 nM; HDAC6: 8 and 14 nM, respectively). In cellular levels, 27f and 39f significantly inhibited cell proliferation of five tumour cell lines (IC50: 0.79 - 4.42 µM). Preliminary mechanistic studies indicated that 27f and 39f efficiently induced cell apoptosis. Unexpectedly, compound 39f could also stimulate cell cycle arrest in G1 phase. Further in vivo study in WSU-DLCL-2 xenografted mouse model validated the antitumor activities of 27f, without significant toxicity. The results suggest the therapeutic potential of these HDACs inhibitors in lymphoma and provide valuable insight and understanding for further structural optimisation around β-elemene scaffold.

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The volatile oils hydrodistilled from the aerial parts and roots of O. carduchorum C.C Towns. (Fabaceae) have been chemically characterized for the first time. A total of 43 constituents with an abundance >0.03% were identified and quantified in the two oils by GC/MS and GC/FID analyses. They comprise 38 components (98.58%) of the oil isolated from the aerial parts (OCA) and 34 components (93.33%) of the oil from the roots (OCR). Six constituents, α-pinene (23.11 ± 0.1%), β-elemene (17.33 ± 0.1%), 1,8-cineole (12.15 ± 0.2%), furfural (7.91 ± 0.1%), terpineol-4-ol (6.32 ± 0.2%), and limonene (4.13 ± 0.1%), accounted for about 75% of the total OCA oil. On the other hand, 1,8-cineole (15.79 ± 0.1%), furfural (10.44 ± 0.1%), β-elemene (10.14 ± 0.2%), α-terpineol (7.74 ± 0.1%), linalool (7.45 ± 0.1%), and α-pinene (4.76 ± 0.1%) made up about 60% of the OCR oil. The IC50 values of the scavenging activities of the OCA and OCR oils towards the DPPH radical and H2O2 were 79.8 ± 0.5 and 153.3 ± 0.6 μg/mL and 394.09 ± 0.2 and 311.67 ± 0.4 μg/mL, respectively. In addition, in the MTS assay, the OCA and OCR oils showed significant antiproliferative effects against T47D, MDA-MB-453, BG-1, and A549 human cancer cells that were more powerful than those against two normal human cell lines, HEK-293 and HFF-1. The abundant presence of β-elemene as an antiproliferative component of the two oils suggested the existence of a new chemotype of O. carduchorum. [ABSTRACT FROM AUTHOR]

Elemene (ELE) is a group of broad-spectrum anticancer active ingredients with low toxicity extracted from traditional Chinese medicines (TCMs), such as Curcumae Rhizoma and Curcuma Radix, which can exert antitumour activities by regulating various signal pathways and targets. However, the strong hydrophobicity, short half-life, low bioavailability and weak in vivo targeting ability of ELE restrict its use. Targeted drug delivery systems based on nanomaterials are among the most viable methods to overcome these shortcomings. In this review, we first summarize recent studies on the clinical uses of ELE as an adjunct antitumour drug. ELE-based combination strategies have great promise for enhancing efficacy, reducing adverse reactions, and improving patients' quality of life and immune function. Second, we summarize recent studies on the antitumour mechanisms of ELE and ELE-based combination strategies. The potential mechanisms include inducing pyroptosis and ferroptosis, promoting senescence, regulating METTL3-mediated m6A modification, suppressing the Warburg effect, and inducing apoptosis and cell cycle arrest. Most importantly, we comprehensively summarize studies on the combination of targeted drug delivery systems with ELE, including passively and actively targeted drug delivery systems, stimuli-responsive drug delivery systems, and codelivery systems for ELE combined with other therapies, which have great promise in improving drug bioavailability, increasing drug targeting ability, controlling drug release, enhancing drug efficacy, reducing drug adverse effects and reversing MDR. Our summary will provide a reference for the combination of TCMs such as ELE with advanced targeted drug delivery systems in the future.

β-Elemene, an active ingredient found in medicinal plants like turmeric and zedoary, is a sesquiterpene compound with antitumor activity against various cancers. However, its current mode of production through plant extraction suffers from low efficiency and limited natural resources. Recently, there has been an increased interest in establishing microbial cell factories to produce germacrene A, which can be converted to β-elemene by a one-step reaction in vitro. In this study, we constructed an engineered Pichia pastoris cell factory for producing germacrene A. We rerouted the fluxes towards germacrene A biosynthesis through the optimization of the linker sequences between germacrene A synthase (GAS) and farnesyl pyrophosphate synthase (ERG20), overexpression of important pathway genes (i.e., IDI1, tHMG1, and ACS), and multi-copy integration of related expression cassettes. In combination with medium optimization and bioprocess engineering, the final titer of germacrene A in a 1 L fermenter reached 1.9 g/L through fed-batch fermentation. This represents the first report on the production of germacrene A in P. pastoris and demonstrates its advantage in producing terpenoids and other value-added natural products. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that β-elemene and compound 5a showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both β-elemene and compound 5a could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose–matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that β-elemene and compound 5a combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death. [ABSTRACT FROM AUTHOR]

Hemangioma (HA) is one of the most common benign vascular tumors among children. Propranolol is used as the first-line treatment for hemangioma and is a non-selective blocker of the β-adrenergic receptor. β-elemene is a compound extracted from Rhizoma zedoariae and has been approved for the treatment of tumors in clinical practice. However, the combinatorial effects of β-elemene and propranolol in the treatment of HA remains unclear. This study explored the combinative effects and mechanisms of β-elemene and propranolol using hemangioma-derived endothelial cells (HemECs). Cytotoxic assays showed that the combinatorial treatment of β- elemene and propranolol did not increase the cytotoxic effects of HemECs. Furthermore, functional analysis showed that the combinatorial treatment with β-elemene and propranolol significantly inhibited the proliferation, migration, and tube formation of the HemECs compared to the single treatment regimens. Mechanistic analysis showed that combinative treatment with β-elemene and propranolol synergistically down-regulated the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor-A (HIF-1-α/VEGFA) signaling pathway. Additionally, in a xenograft tumor model, angiogenesis in the combinatorial treatment group was significantly lower than in the control, propranolol, and β-elemene treatment alone groups. Our results suggest that β-elemene combined with propranolol can significantly inhibit the proliferation, migration, and tube formation of HemECs via synergistically down-regulating the HIF-1-α/VEGFA signaling pathway without increasing any cytotoxic side effects. [ABSTRACT FROM AUTHOR]

Abstract Background β‐elemene is known to play a critical role in tumorigenesis as well as tyrosine kinase inhibitor (TKI) resistance in lung cancer. However, the biological function and molecular mechanism remain largely unknown. Methods In this study, the common genes involved in gefitinib resistance and β‐elemene were identified using bioinformatic analysis. The expression of FBP1 was examined by qRT–PCR and Western blot analysis. Cell proliferation, flow cytometry, clone formation and IC50 assays were performed to assess the effects of β‐elemene and FBP1. Western blot analysis was used to evaluate apoptosis‐related gene expression. Finally, in vivo experiments were conducted to assess the crucial role of FBP1 in gefitinib‐resistant HCC827/GR cells in nude mice. Results Screening analysis demonstrated that fructose‐1,6‐bisphosphatase (FBP1) was induced by β‐elemene and downregulated in gefitinib‐resistant lung cells. Functionally, overexpression of FBP1 inhibited proliferation and gefitinib resistance and promoted apoptosis of PC9/GR and HCC827/GR cells in vitro. Mechanistically, FBP1 impeded the nuclear translocation of p‐STAT3. The FBP1/STAT3 axis was required for FBP1‐mediated apoptosis‐related gene expression. In vivo experiments further confirmed the enhanced effects of FBP1 on lung cancer cell sensitivity to gefitinib. Conclusion Our research indicated that β‐elemene suppressed proliferation and enhanced sensitivity to gefitinib by inducing apoptosis through the FBP1/STAT3 axis in gefitinib‐resistant lung cancer cells.

This study aimed to design and synthesize active hybrids of β‐elemene and nitric oxide (NO) donor pharmacophore as potential agents for treating leukemia. Derivatives reported herein exerted better inhibitory effects against human chronic myeloid leukemia K562 cells compared to β‐elemene (IC50 > 100 μM). The most potent compound 18f showed an IC50 value of 0.53 μM against K562 cells, as well as a high NO release level in vitro. In the K562 xenograft tumor mice model, compound 18f effectively inhibited the growth of the tumor, with a significant inhibition rate of 73.18%. After treatment with compound 18f, the body weight of mice did not decrease, indicating that it possessed good safety profile. All these proved that compound 18f was an excellent potential agent against leukemia. [ABSTRACT FROM AUTHOR]

To study the inhibitory effect of β-elemene on invasion and metastasis of colorectal cancer cells and its possible mechanism. Human colon cancer HCT116 cells were treated with different concentrations of β-elemene. The proliferation inhibition rate of the cells was detected by MTT assay, cell migration rate was detected by scratched assay, and cell invasion rate was evaluated by Transwell cell invasion assay. The expressions of Vimentin, E-cadherin, N-cadherin, and β-catenin were detected by Western blotting. The mRNA expressions of Vimentin, E-cadherin, N-cadherin, and β-catenin were detected by real-time PCR. Compared with the control group, the expressions of migration rate, invasion rate, scratch healing rate, N-cadherin, and Vimentin protein of HCT116 cells were decreased after β-elemene treatment, while the expression of E-cadherin protein was increased, and the inhibition rate of cell proliferation was increased (p<0.05). β-Elemene may inhibit cell proliferation and invasion and metastasis by inhibiting EMT signaling pathway in human colon cancer cell line HCT116. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the chemical compositions of the leaf essential oils of Magnolia villosa (Miq.) H. Keng. and M. maingayi King. growing in Malaysia. The leaf essential oils were obtained by hydrodistillation and fully characterized by gas chromatography and gas chromatography-mass spectrometry. Analysis of M. villosa and M. maingayi leaf essential oils resulted in 96.4% and 98.7% of the total essential oil, respectively. The main components of M. villosa leaf essential oil were β-caryophyllene (32.8%) and α-humulene (8.8%), while in M. maingayi leaf essential oil gave β-elemene (27.4%), β-caryophyllene (16.4%), and (E)-nerolidol (14.4%). Anticholinesterase inhibitory activity was also evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory assays. M. villosa leaf essential oil revealed a moderate inhibitory effect on AChE (percentage inhibition, I%: 62.5%) and BChE (I%: 74.8%) at a concentration of 1,000 μg/mL. In conclusion, the leaf essential oils of M. villosa and M. maingayi were characterized and showed promising anticholinesterase inhibitory activity, suggesting their potential as natural sources of therapeutic agents for managing cholinergic dysfunction-related diseases. [ABSTRACT FROM AUTHOR]

Elemene is a second-line broad-spectrum anti-tumour drug that has been used in China for more than two decades. However, its main anti-tumour ingredient, β-elemene, has disadvantages, including excessive lipophilicity and relatively weak anti-tumour efficacy. To improve the anti-tumour activity of β-elemene, based on its minor molecular weight character, we introduced furoxan nitric oxide (NO) donors into the β-elemene structure and designed six series of new generation β-elemene NO donor hybrids. The synthesised compounds could effectively release NO in vitro, displayed significant anti-proliferative effects on U87MG, NCI-H520, and SW620 cell lines. In the orthotopic glioma model, compound Id significantly and continuously suppressed the growth of gliomas in nude mice, and the brain glioma of the treatment group was markedly inhibited (>90%). In short, the structural fusion design of NO donor and β-elemene is a feasible strategy to improve the in vivo anti-tumour activity of β-elemene.

A series of novel N-alkyl-N-hydroxyl carboximates derived from β-elemene were fortuitously discovered. Most of them showed more potent anti-proliferative activities than their lead compound β-elemene (1). Notably, compound 11i exhibited significant inhibitory effects on the proliferation of three lung cell lines (H1975, A549 and H460) and several other tumour cell lines (H1299, U87MG, MV4-11, and SU-DHL-2). Preliminary mechanistic studies revealed that compound 11i could significantly induce cell apoptosis. Further in vivo study in the H460 xenograft mouse model validated the anti-tumour activities of 11i with a greater tumour growth inhibition (TGI, 68.3%) than β-elemene and SAHA (50.1% and 55.9% respectively) at 60 mg/kg ip dosing, without obvious body weight loss and toxicity. Thus, such N-alkyl-N-hydroxyl carboximate class of compounds exemplified as 11i demonstrated potent anticancer activities both in vitro and in vivo, and should warrant further investigation for potential anticancer therapy.

Abstract Objective To investigate the effect of β-Elemene (β-Ele) on the cisplatin sensitivity of OSCC cells and its mechanism in vitro and in vivo. Methods The human OSCC cell lines Tca-8113 and the cisplatin-resistant cell line Tca-8113-CDDP were cultured with β-Ele or/and cisplatin. The cytotoxicity of cisplatin or β-Ele, cell viability, cell cycles and apoptosis were detected. And the expression of JAK2/STAT3 related protein were detected. The xenograft tumor model of OSCC was established in nude mice and treated with cisplatin and/or β-Ele. The volume and weight of the transplanted tumor was measured, and the expression of p-JAK2 and p-STAT3 and cell apoptosis in the xenograft tumor tissues were detected. Results The combination of β-Ele and cisplatin significantly suppressed the cell proliferation, induced cell cycle arrest, promoted the apoptosis of Tca-8113-CDDP cells, and suppressed the activation of JAK2/STAT3 signaling pathway. The rescue experiments suggested that β-Ele enhanced cisplatin sensitivity via down-regulating JAK2/STAT3 signaling pathway. In vivo, β-Ele and cisplatin synergistically suppressed the tumor growth and induced apoptosis, and down-regulated the expression of p-JAK2 and p-STAT3. Conclusions β-Ele inhibits the cell viability and enhances the cisplatin sensitivity of OSCC by blocking the activation of JAK/STAT3 signaling pathway in vitro and in vivo, and the combination of β-Ele and cisplatin maybe a novel treatment for OSCC.

Breast cancer is a malignant disease with an increasing incidence. Chemotherapy is still an important means for breast cancer treatment, but multidrug resistance (MDR) greatly limits its clinical application. Therefore, the high-efficiency MDR reversal agents are urgently needed. Traditional Chinese medicine (TCM) monomers have unique advantages in reversing chemotherapeutic MDR because of its low toxicity, high efficiency, and ability to impact multiple targets. This review firstly summarizes the major mechanisms of MDR in breast cancer, including the reduced accumulation of intracellular chemotherapeutic drugs, the promoted inactivation of intracellular chemotherapeutic drugs, and the enhanced damage repair ability of DNA, etc., and secondly highlights the research progress of 15 kinds of TCM monomers, including curcumin, resveratrol, emodin, apigenin, tetrandrine, gambogic acid, matrine, paeonol, schisandrin B, β -elemene, astragaloside IV, berberine, puerarin, tanshinone IIA, and quercetin, in reversing MDR of breast cancer. This review also provides the suggestion for the future research of MDR reversal agents in breast cancer. [ABSTRACT FROM AUTHOR]

Bioproduction of natural products via microbial cell factories is a promising alternative to traditional plant extraction. Recently, nonconventional microorganisms have emerged as attractive chassis hosts for biomanufacturing. One such microorganism, Ogataea polymorpha is an industrial yeast used for protein expression with numerous advantages, such as thermal-tolerance, a wide substrate spectrum and high-density fermentation. Here, we systematically rewired the cellular metabolism of O. polymorpha to achieve high-level production of the sesquiterpenoid β-elemene by optimizing the mevalonate pathway, enhancing the supply of NADPH and acetyl-CoA, and downregulating competitive pathways. The engineered strain produced 509 mg/L and 4.7 g/L of β-elemene under batch and fed-batch fermentation, respectively. Therefore, this study identified the potential industrial application of O. polymorpha as a good microbial platform for producing sesquiterpenoids. • Global metabolic rewiring of yeast Ogataea polymorpha enabled the highest β-elemene production of 4.7 g/L. • Systematically optimized the mevalonate pathway for sesquiterpenoid production in O. polymorpha. • Enhanced the supply of cofactor NADPH and precursor acetyl-CoA for isoprenoid biosynthesis in non-conventional yeast. [ABSTRACT FROM AUTHOR]

Citrus is one of the most popular and widely grown fruit crops in the world. However, the bioactivity of only certain species of citrus cultivars is studied. In this study, the effects of essential oils from 21 citrus cultivars on melanogenesis were investigated in an effort to identify active anti-melanogenesis constituents. The essential oils from the peels of 21 citrus cultivars obtained by hydro-distillation were analyzed using gas chromatography–mass spectrometry. Mouse melanoma B16BL6 cells were used in all assays conducted in this study. The tyrosinase activity and melanin content were determined using the lysate of α-Melanocyte-stimulated B16BL6 cells. In addition, the melanogenic gene expression was determined by quantitative reverse transcription-polymerase chain reaction. Overall, the essential oils of (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulata provided the best bioactivity and comprised five distinct constituents compared to other essential oils such as limonene, farnesene, β-elemene, terpinen-4-ol, and sabinene. The anti-melanogenesis activities of the five individual compounds were evaluated. Among the five essential oils, β-elemene, farnesene, and limonene showed dominating properties. The experimental results indicated that (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulara are potential candidates with anti-melanogenesis activity for use as cosmetics and pharmaceutical agents against skin hyperpigmentation. [ABSTRACT FROM AUTHOR]

Background: β‐elemene is known to play a critical role in tumorigenesis as well as tyrosine kinase inhibitor (TKI) resistance in lung cancer. However, the biological function and molecular mechanism remain largely unknown. Methods: In this study, the common genes involved in gefitinib resistance and β‐elemene were identified using bioinformatic analysis. The expression of FBP1 was examined by qRT–PCR and Western blot analysis. Cell proliferation, flow cytometry, clone formation and IC50 assays were performed to assess the effects of β‐elemene and FBP1. Western blot analysis was used to evaluate apoptosis‐related gene expression. Finally, in vivo experiments were conducted to assess the crucial role of FBP1 in gefitinib‐resistant HCC827/GR cells in nude mice. Results: Screening analysis demonstrated that fructose‐1,6‐bisphosphatase (FBP1) was induced by β‐elemene and downregulated in gefitinib‐resistant lung cells. Functionally, overexpression of FBP1 inhibited proliferation and gefitinib resistance and promoted apoptosis of PC9/GR and HCC827/GR cells in vitro. Mechanistically, FBP1 impeded the nuclear translocation of p‐STAT3. The FBP1/STAT3 axis was required for FBP1‐mediated apoptosis‐related gene expression. In vivo experiments further confirmed the enhanced effects of FBP1 on lung cancer cell sensitivity to gefitinib. Conclusion: Our research indicated that β‐elemene suppressed proliferation and enhanced sensitivity to gefitinib by inducing apoptosis through the FBP1/STAT3 axis in gefitinib‐resistant lung cancer cells. [ABSTRACT FROM AUTHOR]

β-Elemene is a valuable sesquiterpene isolated from the essential oil of the traditional Chinese medicine Curcuma wenyujin. As a Chinese class II non-cytotoxic antitumor drug, β-elemene has been broadly used to treat various cancers due to its excellent anti-tumor activity, inhibition of tumor cell migration, and relatively minor adverse effects. Commercial β-elemene is mainly produced via extraction from traditional Chinese medicinal plants and by chemical synthesis. However, limitations in medicinal plant resources and the complexity of chemical synthesis restrict its use given the growing demands. Therefore, it is imperative to identify high-yield biological sources, improve production strategies, develop effective downstream processing, and evaluate the therapeutic applications of β-elemene. Several studies have thoroughly elucidated pathways of β-elemene synthesis in plants and heterologous biosynthesis in microorganisms, which may provide a promising alternative approach for industrial production. The current review aims to discuss the β-elemene biosynthetic pathways and key enzymes involved. Since β-elemene exhibits sensitization properties, and anti-inflammatory and antioxidant effects, recent progress in the understanding of its molecular mechanisms and toxicity, and the application prospects of β-elemene as a medicine have also been critically reviewed here. [ABSTRACT FROM AUTHOR]

Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. β-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that β-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that β-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.

β-Elemene (C15H24), a sesquiterpenoid compound isolated from the volatile oil of Curcuma wenyujin, has been proven to be effective for multiple cancers and is widely used in clinical treatment. Unfortunately, the β-elemene content in C. wenyujin is very low, which cannot meet market demands. Our previous research showed that methyl jasmonate (MeJA) induced the accumulation of β-elemene in C. wenyujin. However, the regulatory mechanism is unclear. In this study, 20 jasmonate ZIM-domain (JAZ) proteins in C. wenyujin were identified, which are the core regulatory factors of the JA signaling pathway. Then, the conservative domains, motifs composition, and evolutionary relationships of CwJAZs were analyzed comprehensively and systematically. The interaction analysis indicated that CwJAZs can form homodimers or heterodimers. Fifteen out of twenty CwJAZs were significantly induced via MeJA treatment. As the master switch of the JA signaling pathway, the CwMYC2-like protein has also been identified and demonstrated to interact with CwJAZ2/3/4/5/7/15/17/20. Further research found that the overexpression of the CwMYC2-like gene increased the accumulation of β-elemene in C. wenyujin leaves. Simultaneously, the expressions of HMGR, HMGS, DXS, DXR, MCT, HDS, HDR, and FPPS related to β-elemene biosynthesis were also up-regulated by the CwMYC2-like protein. These results indicate that CwJAZs and the CwMYC2-like protein respond to the JA signal to regulate the biosynthesis of β-elemene in C. wenyujin.

Background: Gynecological cancers encompass all uncontrolled and aberrant cell growth in the female reproductive system, therapeutic interventions are constantly evolving, but there is still a high death rate, significant side effects and medication resistance, making the task of treatment challenging and complex. The essential oil extracted from the rhizome of Curcuma longa is a promising natural drug, which has excellent biological activity on cancer cells and is to be developed as a new type of anti-gynecological tumor therapeutic agent. Purpose: To systematically summarize the available evidence for the efficacy of Curcuma oil and its terpenoids (β-elemene, curcumol, furanodiene, and germacrone) in gynecological cancers, primarily malignancies of the reproductive system, involving ovarian, cervical, and endometrial cancers, explain the underlying mechanisms of preventing and treating gynecological cancers, and assess the shortcomings of existing work. Results: Through several signaling channels, Curcuma oil and its terpenoids can not only stop the growth of ovarian cancer, cervical cancer, and endometrial cancer cells, limit the formation of tumors, but also raise the effectiveness of chemotherapy drugs and improve the quality of life for patients. Conclusion: It provides a preclinical basis for the efficacy of Curcuma oil as a broad-spectrum anti-tumor agent for the prevention and treatment of gynecological cancers. Even so, further efforts are still needed to improve the bioavailability of Curcuma oil and upgrade related experiments.

The pathology of psoriasis involves the over-proliferation of keratinocytes, exaggerated inflammation of keratinocytes, and infiltration of inflammatory cells such as macrophages (Mø), etc. The therapeutic outcomes of current treatment targeting one single pathological process are less than satisfactory. Based on their diverse biological activities, natural products offer a potential solution to this problem. In this study, we investigated the effects of β-Elemene (ELE) on both psoriatic keratinocytes and M1-type Mø (M1-Mø) in vitro. Hyaluronic acid (HA) microneedles loaded with ELE (HA-ELE-MN) were also fabricated and tested for the treatment of psoriasis in vivo using an imiquimod (IMQ)-induced psoriatic mice model. Our data suggest that ELE induces apoptosis and inhibits inflammation of psoriatic keratinocytes. In addition, ELE attenuates the expression of inflammatory cytokines secreted from M1-Mø, thus indirectly inhibiting the inflammation of keratinocytes. Furthermore, HA-ELE-MN has been found to significantly alleviate symptoms in an IMQinduced psoriatic mice model by inducing keratinocytes apoptosis, suppressing keratinocytes proliferation, and inhibiting M1-Mø infiltration. Taken together, this study demonstrates that ELE can be used for the treatment of psoriasis by targeting both keratinocytes and M1-Mø, which provides a potential novel reagent for psoriasis treatment. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that β-elemene and compound 5a showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both β-elemene and compound 5a could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose–matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that β-elemene and compound 5a combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death.

Neuropathic pain takes a heavy toll on individual well-being, while current therapy is far from desirable. Herein, we assessed the analgesic effect of β-elemene, a chief component in the traditional Chinese medicine Curcuma wenyujin, and explored the underlying mechanisms at the level of spinal dorsal horn (SDH) under neuropathic pain. A spared nerve injury (SNI)-induced neuropathic pain model was established in rats. Intraperitoneal injection (i.p.) of β-elemene was administered for 21 consecutive days. Mechanical allodynia was explored by von Frey filaments. The activation of the mitogen-activated protein kinase (MAPK) family (including ERK, p38, and JNK) in spinal neurons, astrocytes, and microglia was evaluated using immunostaining 29 days after SNI surgery. The expression of GFAP, Iba-1, p-ERK, p-JNK, and p-p38 within the SDH was measured using immunoblotting. The levels of proinflammatory cytokines (including TNF-α, IL-1β, and IL-6) were measured with ELISA. The levels of oxidative stress indicators (including MDA, SOD, and GSH-PX) were detected using biochemical tests. Consecutive i.p. administration of β-elemene relieved SNI-induced mechanical allodynia (with an EC50 of 16.40 mg/kg). SNI significantly increased the expression of p-ERK in spinal astrocytes but not microglia on day 29. β-elemene reversed spinal astrocytic ERK activation and subsequent upregulation of proinflammatory cytokines in SNI rats, with no effect on the expression of p38 and JNK in spinal glia. β-elemene also exerted antioxidative effects by increasing the levels of SOD and GSH-PX and decreasing the level of MDA. Our results suggest that SNI induces robust astrocytic ERK activation within the SDH in the late phase of neuropathic pain. β-elemene exerts remarkable analgesic effects on neuropathic pain, possibly by inhibiting spinal astrocytic ERK activation and subsequent neuroinflammatory processes. Our findings suggest that β-elemene might be a promising analgesic for the treatment of chronic pain. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of β-Elemene (β-Ele) on the cisplatin sensitivity of OSCC cells and its mechanism in vitro and in vivo. Methods: The human OSCC cell lines Tca-8113 and the cisplatin-resistant cell line Tca-8113-CDDP were cultured with β-Ele or/and cisplatin. The cytotoxicity of cisplatin or β-Ele, cell viability, cell cycles and apoptosis were detected. And the expression of JAK2/STAT3 related protein were detected. The xenograft tumor model of OSCC was established in nude mice and treated with cisplatin and/or β-Ele. The volume and weight of the transplanted tumor was measured, and the expression of p-JAK2 and p-STAT3 and cell apoptosis in the xenograft tumor tissues were detected. Results: The combination of β-Ele and cisplatin significantly suppressed the cell proliferation, induced cell cycle arrest, promoted the apoptosis of Tca-8113-CDDP cells, and suppressed the activation of JAK2/STAT3 signaling pathway. The rescue experiments suggested that β-Ele enhanced cisplatin sensitivity via down-regulating JAK2/STAT3 signaling pathway. In vivo, β-Ele and cisplatin synergistically suppressed the tumor growth and induced apoptosis, and down-regulated the expression of p-JAK2 and p-STAT3. Conclusions: β-Ele inhibits the cell viability and enhances the cisplatin sensitivity of OSCC by blocking the activation of JAK/STAT3 signaling pathway in vitro and in vivo, and the combination of β-Ele and cisplatin maybe a novel treatment for OSCC. [ABSTRACT FROM AUTHOR]

(-)-β-Elemene is a primary bioactive compound derived from Curcuma wenyujin and has been widely utilized as an anti-tumor agent for various types of cancer. Due to the inefficiency of plant extraction methods for β-elemene, significant efforts have been directed toward the heterogeneous biosynthesis of β-elemene using microbial cell factories. However, there has been less emphasis on the stereochemical configuration of germacrene A and its rearranged product, β-elemene. In this study, we constructed a yeast cell factory to produce (-)-β-elemene by optimizing the mevalonate pathway and screening for germacrene A synthases (GASs) from both plant and microbial sources. Notably, we discovered that the rearranged products of GASs exhibited different conformations, and only (+)-germacrene A produced by plant-derived GASs could rearrange to form (-)-β-elemene. Building on this discovery, we further investigated the catalytic mechanisms of GASs and developed an efficient catalytic gene module for generating (+)-germacrene A. Ultimately, the engineered yeast produced 1152 mg/L of (-)-β-elemene, marking the highest titer reported in yeast to date. Overall, this work highlights the differences in the stereoconformations of catalytic products between plant- and microbial-derived germacrene A synthases and establishes a foundation for the green and efficient production of β-elemene with a specific stereochemical configuration., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)