Exosomes Mediate the Production of Oxaliplatin Resistance and Affect Biological Behaviors of Colon Cancer Cell Lines.

BACKGROUND: Colon cancer has high mortality rate which making it one of the leading causes of cancer deaths. Oxaliplatin is a common chemotherapeutic drug, but it has disadvantages such as drug resistance. OBJECTIVE: The purpose of this study is to explore the mechanism of exosomes in the resistance of oxaliplatin and verify whether elemene and STAT3 inhibitors reverse the resistance to oxaliplatin. METHODS: Related cell line models were constructed and the proliferation, migration, invasion, apoptosis and resistance to oxaliplatin were evaluated for all three cells of HCT116/L, sensitive cell HCT116 and HCT116+HCT116/L-exosomes (HCT116-exo). It was to explore probable signaling pathways and mechanisms by Western blotting. RESULTS: HCT116-exo drug-resistant chimeric cells showed greater capacity for proliferation, migration and invasion than HCT116 sensitive cells. After the above cells were treated with oxaliplatin, the apoptosis rate of chimeric drug-resistant cells HCT116-exo and its IC50 increased compared with the sensitive cells HCT116. The proliferation, invasion and migration of cells treated with STAT3 inhibitor or ß-elemene combined with oxaliplatin reduced compared with those treated with oxaliplatin or ß-elemene alone. The STAT3 inhibitor or ß-elemene in combination with oxaliplatin increased the rate of apoptosis relative to oxaliplatin or ß-elemene alone. Drug-resistant cell exosomes could promote the EMT process, related to the participation of FGFR4, SHMT2 and STAT3 inhibitors. CONCLUSION: Drug-resistant cell exosomes could induce resistance, and improve the capacity of colon cancer towards proliferate, invade, migrate and promote the EMT process. The ß-elemene combined with oxaliplatin could reverse the above results which might be related to the STAT3 pathway and EMT pathway in colon cancer.

ß-elemene promotes microglial M2-like polarization against ischemic stroke via AKT/mTOR signaling axis-mediated autophagy.

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. ß-elemene is a natural sesquiterpene and possesses potent anti-inflammatory activity. This study aimed to investigate the anti-inflammatory efficacy and mechanism of ß-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 ß-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 ß-elemene regulating M1/M2-like polarization in vitro. RESULTS: In C57BL/6 J mice subjected to MCAO model and photothrombotic stroke model, ß-elemene attenuated neurological deficit, reduced the infarction volume and neuroinflammation, thus improving ischemic stroke injury. ß-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, ß-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 ß-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 ß-elemene might serve as a promising drug for alleviating ischemic stroke injury.

Elemene Injection Overcomes Paclitaxel Resistance in Breast Cancer through AR/RUNX1 Signal: Network Pharmacology and Experimental Validation.

BACKGROUND: Paclitaxel (PTX) is a cornerstone chemotherapy for Breast Cancer (BC), yet its impact is limited by emerging resistance. Elemene Injection (EI) has shown potential in overcoming chemotherapy resistance. However, the efficacy by which EI restores PTX sensitivity in BC and the implicated molecular mechanism remain uncharted. METHODS: Network pharmacology and bioinformatic analysis were conducted to investigate the targets and mechanisms of EI in overcoming PTX resistance. A paclitaxel-resistant MCF-7 cell line (MCF-7PR) was established. The efficacy of EI and/or PTX in inhibiting cell viability was evaluated using sulforhodamine B assay, while cell proliferation was assessed using EdU staining. Furthermore, protein and gene expression analysis was performed through Western blotting and qPCR. RESULTS: The EI containing three active components exhibited a multifaceted impact by targeting an extensive repertoire of 122 potential molecular targets. By intersecting with 761 differentially expressed genes, we successfully identified 9 genes that displayed a direct association with resistance to PTX in BC, presenting promising potential as therapeutic targets for the EI to effectively counteract PTX resistance. Enrichment analysis indicated a significant correlation between these identified targets and critical biological processes, particularly DNA damage response and cell cycle regulation. This correlation was further substantiated through meticulous analysis of single-cell datasets. Molecular docking analysis revealed robust binding affinities between the active components of the EI and the identified molecular targets. Subsequently, in vitro experiments unequivocally demonstrated the dose- and time-dependent inhibitory effects of the EI on both PTX-resistant and sensitive BC cell lines, effectively mitigating the resistance phenotype associated with PTX administration. Furthermore, our findings have indicated EI to effectively suppress the protein expression levels of AR and RUNX1 in MCF-7 and MCF-7PR cells under PTX treatment, as well as downregulate the mRNA expression levels of stem-like properties' markers, KLF4 and OCT4, in these cell lines. CONCLUSION: Elemene Injection (EI) application has exhibited a significant capability to mitigate PTX resistance in BC, which has been achieved through targeted suppression of the AR/RUNX1 axis, revealing a key strategy to overcome chemotherapeutic resistance.

Recent advances in lycopene and germacrene a biosynthesis and their role as antineoplastic drugs.

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 ß-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.

Effect of black cloth ointment on hypertrophic scar formation: An investigation using integrated network pharmacology and animal assay.

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 ß-elemene on HS. Finally, the molecular mechanism of BCO and ß-elemene was analyzed by Western blot. RESULTS: Through the network pharmacology, it showed that ß-elemene was the main active ingredient of BCO, and it could significantly improve the pathological structure of HS and reduce collagen deposition. BCO and ß-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 ß-elemene, and cellular apoptosis is the key mechanism through which the BCO and ß-elemene exert their effects.

[Preparation and characterization of co-loaded indocyanine green and elemene nano-emulsion in situ gel and its effect on proliferation of breast cancer MCF-7 cells].

This study aims to prepare co-loaded indocyanine green(ICG) and elemene(ELE) nano-emulsion(NE) in situ gel(ICG-ELE-NE-gel) and evaluate its physicochemical properties and antitumor activity in vitro. ICG-ELE-NE-gel was prepared by aqueous phase titration and cold solution methods, followed by characterization of the morphology, particle size, corrosion, and photothermal conversion characteristics. The human breast cancer MCF-7 cells were taken as the model, combined with 808 nm laser irradia-tion. Cell inhibition rate test and cell uptake test were performed. ICG-ELE-NE was spherical and uniform in size. The average particle size and Zeta potential were(85.61±0.35) nm and(-21.4±0.6) mV, respectively. The encapsulation efficiency and drug loading rate were 98.51%±0.39% and 10.96%±0.24%, respectively. ICG-ELE-NE-gel had a good photothermal conversion effect and good photothermal stability. The dissolution of ICG-ELE-NE-gel had both temperature and pH-responsive characteristics. Compared with free ELE, ICG-ELE-NE-gel combined with near-infrared light irradiation significantly enhanced the inhibitory effect on MCF-7 cells and could be uptaken in large amounts by MCF-7 cells. ICG-ELE-NE-gel was successfully prepared, and its antitumor activity was enhanced after 808 nm laser irradiation.

ß-Elemene Reverses Gefitinib Resistance in NSCLC Cells by Inhibiting lncRNA H19-Mediated Autophagy.

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. ß-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between ß-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether ß-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and ß-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 ß-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, ß-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, ß-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. ß-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.

ß-elemene alleviates esophageal fibrosis after endoscopic submucosal dissection via the FAP-mediated PTEN-PI3K/AKT signaling pathway.

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. ß-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 ß-elemene in esophageal fibrosis by treating primary human esophageal granulation fibroblasts (PHEGFs) with gradient concentrations of ß-elemene. Our findings demonstrated that ß-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 ß-elemene in relieving esophageal fibrosis and offer novel therapeutic strategies for managing post-esophageal ESD stricture in clinical practice.

Prevalence of inappropriateness of elemene injection for hospitalized cancer patients: a multicenter retrospective study.

Background: Elemene injection could provide clinical benefit for the treatment of various cancers, but the clinical evidence is weak. Thus, its wide use in China has raised concerns about the appropriateness of its use. Methods: This was a multicenter retrospective study to evaluate the prevalence of inappropriateness of elemene injection for hospitalized cancer patients. Patients who met the inclusion criteria were retrospectively included, and demographic characteristics were extracted from the hospital information systems. The inappropriateness of elemene injection use was assessed using the preset criteria, and the prevalence was calculated. Multivariate logistic analysis was applied to identify any factors associated with inappropriate use. Results: A total of 275 patients were included in the analysis. The median age was 62 years, and 30.9% were females. The most common cancer was lung cancer (24.0%), and 68.2% of the patients were receiving chemotherapy. The overall prevalence of inappropriateness was 61.8%. The most common reason for inappropriateness was inappropriate indications, and the second was inappropriate doses. Age and oncological department were significant risk factors associated with inappropriate use, while lung cancer, liver cancer and admission to cardiothoracic surgery were associated with a low risk of inappropriate use. Conclusion: The prevalence of inappropriateness among hospitalized elemene injection users was high. More efforts, especially those to improve the appropriateness of indications, should be made to improve the rational use of elemene, as well as other complementary medicines. Physicians should take caution to avoid inappropriate use when prescribing drugs with limited clinical evidence.

Beta-elemene: A phytochemical with promise as a drug candidate for tumor therapy and adjuvant tumor therapy.

BACKGROUND: ß-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 ß-elemene research, with respect to disease treatment. METHODS: ß-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 ß-elemene. We further combined these targets with the relevant literature for KEGG and GO analyses. RESULTS: Studies on the molecular mechanisms underlying ß-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-ß/Smad signaling. Through these molecular pathways, ß-elemene has been implicated in tumor cell proliferation, apoptosis, migration, and invasion and improving the immune microenvironment. Additionally, ß-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: ß-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, ß-elemene has vast potential for research and development.

Analysis of root volatiles and functional characterization of a root-specific germacrene A synthase in Artemisia pallens.

MAIN CONCLUSION: The study demonstrated that Artemisia pallens roots 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 ß-elemene, neryl isovalerate, ß-selinene, and α-selinene, and trace amounts of monoterpenes ß-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 ß-elemene and germacrene A with E,E-farnesyl diphosphate (FPP) as a substrate. Detailed analysis of assay products revealed that ß-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.

Chemotherapeutic drug elemene induces pain and anxiety-like behaviors by activating GABAergic neurons in the lateral septum of mice.

Most chemotherapeutic drugs are potent and have a very narrow range of dose safety and efficacy, most of which can cause many side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and serious side effect of chemotherapy for cancer treatment. However, its mechanism of action is yet to be fully elucidated. In the present study, we found that the treatment of the chemotherapy drug elemene induced hyperalgesia accompanied by anxiety-like emotions in mice based on several pain behavioral assays, such as mechanical allodynia and thermal hyperalgesia tests. Second, immunostaining for c-fos (a marker of activated neurons) further showed that elemene treatment activated several brain regions, including the lateral septum (LS), cingulate cortex (ACC), paraventricular nucleus of the thalamus (PVT), and dorsomedial hypothalamic nucleus (DMH), most notably in the GABAergic neurons of the lateral septum (LS). Finally, we found that both chemogenetic inhibition and apoptosis of LS neurons significantly reduced pain- and anxiety-like behaviors in mice treated with elemene. Taken together, these findings suggest that LS is involved in the regulation of elemene-induced chemotherapy pain and anxiety-like behaviors, providing a new target for the treatment of chemotherapy pain induced by elemene.

ß-elemene enhances cisplatin sensitivity of non-small cell lung cancer cells via the miR-17-5p/STAT3 axis.

In China, ß-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 ß-elemene in regulating cisplatin sensitivity of NSCLC cells and the related mechanisms are not clear. This study was conducted to investigate the role of ß-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, ß-elemene inhibits the viability, and induces the apoptosis of cisplatin-resistant NSCLC cells. Additionally, ß-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 ß-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 ß-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.

Elemene Antitumor Drugs Development Based on "Molecular Compatibility Theory" and Clinical Application: A Retrospective and Prospective Outlook.

Elemene, derived from Curcuma wenyujin, one of the "8 famous genuine medicinal materials of Zhejiang province," exhibits remarkable antitumor activity. It has gained wide recognition in clinical practice for effectiveness on tumors. Dr. XIE Tian, introduced the innovative concept of "molecular compatibility theory" by combining Chinese medicine principles, specifically the "monarch, minister, assistant, and envoy" theory, with modern biomedical technology. This groundbreaking approach, along with a systematic analysis of Chinese medicine and modern biomedical knowledge, led to the development of elemene nanoliposome formulations. These novel formulations offer numerous advantages, including low toxicity, well-defined composition, synergistic effects on multiple targets, and excellent biocompatibility. Following the principles of the "molecular compatibility theory", further exploration of cancer treatment strategies and methods based on elemene was undertaken. This comprehensive review consolidates the current understanding of elemene's potential antitumor mechanisms, recent clinical investigations, advancements in drug delivery systems, and structural modifications. The ultimate goal of this review is to establish a solid theoretical foundation for researchers, empowering them to develop more effective antitumor drugs based on the principles of "molecular compatibility theory".

ß-Elemene in zedoary turmeric oil injection induces dyspnea by binding to hemoglobin and upregulating HIF-1α.

ETHNOPHARMACOLOGICAL RELEVANCE: Zedoary turmeric oil injection (ZTOI) extracted from the rhizome extract of Curcuma phaeocaulis Valeton, Curcuma wenyujin Y. H. Chen et C. Ling or Curcuma kwangsiensis S. G. Lee et C. F. Liang, is widely used for the treatment of virus-induced upper respiratory tract infections, peptic ulcers, viral pneumonia, etc. However, it has attracted widespread attention because it often causes adverse drug reactions (ADRs), including dyspnea. However, little is known about the mechanism underlying dyspnea caused by ZTOI, which limits its clinical application. AIM OF THE STUDY: To investigate the major pathophysiologic signatures and underlying mechanism of ZTOI-related dyspnea. METHODS: Respiratory function detection was used to explore the pathophysiologic signature of dyspnea induced by ZTOI. UV-vis absorption spectroscopy and isothermal titration calorimetry were applied to test the interaction between ZTOI and hemoglobin (Hb). GC‒MS was used to identify the main components in ZTOI. Molecular docking, surface plasmon resonance, and circular dichroism spectroscopy were employed to test the reaction between ß-elemene and Hb. Western blot was performed to investigate the effect of ß-elemene on the hypoxia signaling pathway. RESULTS: The results showed that ZTOI-induced dyspnea was related to a decreased oxygen carrying capacity of Hb. The molecular interaction between ZTOI and Hb was proven. Notably, ß-elemene in ZTOI exhibited high binding affinity to Hb and altered its secondary structure. Furthermore, it was found that ß-elemene downregulated the expression of prolyl hydroxylase-domain protein 2 and upregulated the expression of hypoxia-inducible factor-1α. CONCLUSIONS: Our study is valuable for better understanding the pathophysiological characteristics and underlying mechanism of ZTOI to ensure its safe clinical application. We also provided a strategy to elucidate the underlying mechanism based on inspiration from clinical ADR phenotypes for investigating other medical products with ADRs in the clinic.

Elemene Antitumor Drugs Development Based on "Molecular Compatibility Theory" and Clinical Application: A Retrospective and Prospective Outlook / 中国结合医学杂志

Elemene, derived from Curcuma wenyujin, one of the "8 famous genuine medicinal materials of Zhejiang province," exhibits remarkable antitumor activity. It has gained wide recognition in clinical practice for effectiveness on tumors. Dr. XIE Tian, introduced the innovative concept of "molecular compatibility theory" by combining Chinese medicine principles, specifically the "monarch, minister, assistant, and envoy" theory, with modern biomedical technology. This groundbreaking approach, along with a systematic analysis of Chinese medicine and modern biomedical knowledge, led to the development of elemene nanoliposome formulations. These novel formulations offer numerous advantages, including low toxicity, well-defined composition, synergistic effects on multiple targets, and excellent biocompatibility. Following the principles of the "molecular compatibility theory", further exploration of cancer treatment strategies and methods based on elemene was undertaken. This comprehensive review consolidates the current understanding of elemene's potential antitumor mechanisms, recent clinical investigations, advancements in drug delivery systems, and structural modifications. The ultimate goal of this review is to establish a solid theoretical foundation for researchers, empowering them to develop more effective antitumor drugs based on the principles of "molecular compatibility theory".

Targeted metabolomics reveals PFKFB3 as a key target for elemene-mediated inhibition of glycolysis in prostate cancer cells.

BACKGROUND: Elemene, an active anticancer extract derived from Curcuma wenyujin, has well-documented anticarcinogenic properties. Nevertheless, the role of elemene in prostate cancer (PCa) and its underlying molecular mechanism remain elusive. PURPOSE: This study focuses on investigating the anti-PCa effects of elemene and its underlying mechanisms. METHODS: Cell-based assays, including CCK-8, scratch, colony formation, cell cycle, and apoptosis experiments, to comprehensively assess the impact of elemene on PCa cells (LNCaP and PC3) in vitro. Additionally, we used a xenograft model with PC3 cells in nude mice to evaluate elemene in vivo efficacy. Targeted metabolomics analysis via HILIC-MS/MS was performed to investigate elemene potential target pathways, validated through molecular biology experiments, including western blotting and gene manipulation studies. RESULTS: In this study, we discovered that elemene has remarkable anti-PCa activity in both in vitro and in vivo settings, comparable to clinical chemotherapeutic drugs but with fewer side effects. Using our established targeted metabolomics approach, we demonstrated that ß-elemene, elemene's primary component, effectively inhibits glycolysis in PCa cells by downregulating 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression. Furthermore, we found that ß-elemene accomplishes this downregulation by upregulating p53 and FZR1. Knockdown and overexpression experiments conclusively confirmed the pivotal role of PFKFB3 in mediating ß-elemene's anti-PCa activity. CONCLUSION: This finding presents compelling evidence that elemene exerts its anti-PCa effect by suppressing glycolysis through the downregulation of PFKFB3. This study not only improves our understanding of elemene in PCa treatment but also provides valuable insights for developing more effective and safer therapies for PCa.

Discovery and bioassay of disubstituted ß-elemene-NO donor conjugates: synergistic enhancement in the treatment of leukemia.

Natural products are essential sources of antitumor drugs. One such molecule, ß-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 ß-elemene derivatives were designed, with ß-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.

The complementary and alternative roles of elemene injection in cancer: An umbrella review.

BACKGROUND: In the past, many meta-analyses (MAs) suggested that elemene injection (EI) played a complementary and alternative role in cancer treatment. However, some results were contradictory and a lot of evidences weren't classified. Thus, their clinical guidance effect was very limited. METHODS: Two reviewers independently retrieved 8 databases from their origin to May 19, 2023 and appropriate MAs were taken into consideration. A pooled analysis was conducted to merge results extracted from trials of included MAs. The methodological quality of MAs and the evidence certainty of pooled results were assessed. RESULTS: 31 MAs were taken into analysis with poor methodological quality. The main weaknesses were in the areas of heterogeneity analysis, bias risk, and literature selection. According to the present evidence, on the one hand, compared with conventional treatment (CT) alone, EI combined with CT may significantly enhance short-term or long-term efficacy and reduce adverse reactions caused by CT in multiple cancers. On the other hand, using EI alone also can improve ORR in the malignant (pleural) effusion and lessen the recurrence rate in bladder cancer obviously with fewer adverse reactions compared with CT alone. However, this evidence was rated as moderate to very low certainty mainly due to the risk of bias in clinical trials. CONCLUSION: EI may be a viable medication for the treatment of cancer although more convincing trials are still required to demonstrate its alternative and complementary benefits. Besides, it seems to have a broad potential for further development in immunotherapy, drug delivery technique, and predictive factor.

A review of traditional Chinese medicine Curcumae Rhizoma for treatment of glioma.

Glioma is the most common primary central nervous tumor and its malignant and high recurrence rate are seriously threatening patient's life. The prognosis of glioma patients is still poor with a variety of modern treatments. Traditional Chinese medicine (TCM) is widely used in the adjuvant treatment or alternative medicine of glioma. Curcumae Rhizoma is one of the most commonly used in traditional Chinese medicine prescriptions for its anti-tumor characteristics. There are also many studies that reveals the anti-tumor effect of its active ingredients and some of which have been made into drugs and have been used in clinical practice. This review summarizes the new research progress on Curcumae Rhizoma for the treatment of glioma in recent years.