Dynamic deracemization processes, such as crystallization‐induced diastereomer transformations (CIDTs), offer the opportunity to combine racemization and resolution processes, to provide high yields ...of enantiomerically pure compounds. To date, few of these processes have incorporated photochemical racemization. By combining batch crystallization with a flow photoreactor for efficient irradiation, it is possible to perform such deracemization in an effective, scalable and high yielding manner. After applying design of experiment (DoE) principles and mathematical modelling, the most efficient parameter set could be identified, leading to excellent results in just 4 h reaction time: isolated yield of 82 % and assay ee of 96 %. Such photochemical racemization methods can serve to open new avenues for preparation of enantiomerically pure functional molecules on both small and industrially‐relevant scales.
Photo‐transformation: Unlike classical enantiomeric resolution methods, crystallization‐induced diastereomer transformations (CIDTs) allow full conversion to the desired enantiomer. Using photochemical racemization for a CIDT has not before been published in the scientific literature. We report the use of an oscillatory flow reactor for efficient irradiation, allowing high yield and >95 % ee to be achieved in a reaction time of just a few hours.
Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel ...targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.
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•Drug screening identified effective drugs for uterine leiomyosarcoma (ULMS).•Proscillaridin A and lanatoside C showed antitumor effects in vivo.•RNA sequencing revealed the downregulation of UCP2 in the sirtuin signaling pathway.•UCP2 silencing inhibited ULMS cell growth and increased ROS production.•UCP2 was overexpressed in human ULMS tissues than in myoma tissues.
Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs ...(miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function.
Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients.
miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2.
miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts.
•Small RNA sequencing revealed uterine leiomyosarcoma-specific miRNA profiles.•Uterine leiomyosarcoma cells secrete extracellular vesicles with specific miRNAs.•The extracellular vesicles induce the features of cancer-associated fibroblasts.
Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of ...the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines.
ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis.
ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients.
ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.
•ADSC-sEVs showed stronger antitumor effects on ovarian cancer cell lines compared to ADSC-m/lEVs.•Transcriptome analysis indicated the involvement of let-7 family in the antitumor effect.•BACH1, COIL, MAP4K3, and PAPPA were identified as target genes of hsa-let-7b-5p and hsa-let-7e-5p.
