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Simple Summary: Colorectal cancer (CRC) claimed more than 900,000 lives globally in 2020. Therefore, its pathogenetic landscape calls for in-depth investigation. Recently, more attention has been paid to oncogenesis driven by noncoding RNAs and even peptides encoded by noncoding RNAs. Here, we report a LINC01234-encoded peptide named MEK1-binding oncopeptide (MBOP), which exists endogenously and is highly expressed in CRC. Through in vivo and in vitro migration and proliferation assays, we demonstrated the oncogenic role of MBOP. In addition, we performed immunoprecipitation assays to identify the interacting proteins and pathways, and MBOP was found to interact with MEK1 and activate the MEK1/pERK/MMP2/MMP9 signaling pathway. Moreover, the ubiquitin–protease-system-mediated degradation of MBOP was elucidated, where the E3 ubiquitin-protein transferase MAEA and RMND5A play vital roles. In conclusion, oncopeptide MBOP plays a substantial role in the tumorigenesis of CRC, and it could be a candidate prognostic biomarker for clinical treatment. Colorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded from LINC01234 was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin–protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC. [ABSTRACT FROM AUTHOR]

Resveratrol, a common polyphenol, has extensive pharmacological activities. Resveratrol inhibits some steroid biosynthetic enzymes, indicating that it may block neurosteroid synthesis. The objective of the present study is to investigate the inhibition of resveratrol on neurosteroidogenic enzymes rat 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C9), and retinol dehydrogenase 2 (RDH2). The IC 50 values of resveratrol on SRD5A1, AKR1C9, and RDH2 were > 100 μM, 0.436 ± 0.070 μM, and 4.889 ± 0.062 μM, respectively. Resveratrol competitively inhibited rat AKR1C9 and RDH2 against steroid substrates. Docking showed that resveratrol bound to the steroid binding pocket of AKR1C9. It exerted a mixed mode on these AKR1C9 and RDH2 against cofactors. In conclusion, resveratrol potently inhibited rat AKR1C9 and RDH2 to regulate local neurosteroid levels. [ABSTRACT FROM AUTHOR]

Pharmacophore-probe reaction guided purification strategy can reduce the workload of natural product chemistry and raise the probability of obtaining undescribed and high-bioactive target compounds. In this study, a probe of N -acetyl cysteine (NAC) was used to confirm the pharmacophore of Tubocapsicum anomalum (Franch. et Sav.) Makino. Furthermore, a thiol probe named 4-bromothiophenol (BTP) guided the discovery of three undescribed (1–3) and nine known (4–12) electrophilic withanolides (EWs) featured potential anti-triple negative breast cancer (TNBC) pharmacophore. Notably, co-incubation with BTP made the single crystals of EW conjugates much more accessible, which facilitated the absolute configuration determination of EWs. Electrophilic natural products with the potential of thio-alkylation modification and covalent inhibition key proteins in tumor cell signal transduction pathways may display significant antitumor activity. The MTT results indicated that most EWs showed anti-TNBC activity and were expected to develop anti-TNBC candidate drugs with high selectivity and novel mechanism. [Display omitted] • Pharmacophore-probe reaction guided precision discovery strategy is reported. • Three undescribed withanolides were identified of which the structure of 1 is rare. • Four known withanolides exhibited significant anti-TNBC activity in vitro. • It may be a novel method to determine the absolute configuration of EWs using BTP. [ABSTRACT FROM AUTHOR]