Author: Zhao, Yingyi ; Yao, Qing ; Zhu, Qibing ; Zhou, Shengjie ; Chen, Mei ; Ding, Yang ; Huang, Chengbo ; Chen, Fengyun ; Wang, Jiakun ; Wang, Yi ; Li, Lifeng ; Chen, Nuo ; Zhu, Yuhao ; Lv, Leyao

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.

01 Nov 2024·International Journal of Biological Macromolecules

Screening and modification of (+)-germacrene A synthase for the production of the anti-tumor drug (−)-β-elemene in engineered Saccharomyces cerevisiae

Article

Author: Yin, Xiaopu ; Bai, Xue ; Wei, Qiuhui ; Ma, Jing ; Men, Lianhui ; Xie, Tian ; Xu, Mengdie ; Zhang, Qin ; Wang, Daming ; Li, Dengyu ; Chen, Rong ; Hu, Tianyuan ; Hu, Yuhan

(-)-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.

01 Oct 2024·Food and Chemical Toxicology

RIFM fragrance ingredient safety assessment, furfural, CAS Registry Number 98-01-1

Review

Author: Jones, L ; Sipes, I G ; Muldoon, J ; Bartlett, A ; Belsito, D ; Schember, I ; Bryant-Freidrich, A ; Thakkar, Y ; Api, A M ; Burton, G A ; Lavelle, M ; Penning, T M ; Joshi, K ; Ritacco, G ; Botelho, D ; Dagli, M L ; Lapczynski, A ; Tokura, Y ; Sadekar, N ; Moustakas, H ; Schultz, T W ; Deodhar, C ; Lee, I ; Fryer, A D ; Chon, H ; Farrell, K ; Cancellieri, M A ; Siddiqi, F ; Dekant, W ; Bruze, M ; Sullivan, G

A review.β-Ionol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety.Data show that β-ionol is not genotoxic. Data on read-across analog (E)-β-ionone (CAS # 79-77-6) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints.Data from read-across analog β-irone (CAS # 79-70-9) provided β-ionol a No Expected Sensitization Induction Level (NESIL) of 1700 Μg/cm² for the skin sensitization endpoint.The photoirritation/photoallergenicity endpoints were evaluated based on UV/visible (UV/Vis) spectra; β-ionol is not expected to be photoirritating/photoallergenic.For the local respiratory endpoint, a calculated MOE >100 was provided by the read-across analog β-ionone (CAS # 14901-07-6).The environmental endpoints were evaluated; β-ionol was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA)Environmental Standards, and its risk quotients, based on its current Volume of Use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are,<1.

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Cancer	Preclinical	CN	The First Hospital Of China Medical University	01 Jul 2018

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