Development of a novel six DNA damage response-related prognostic signature in osteosarcoma.

DNA damage response (DDR) plays a vital role in the development of cancer. Nevertheless, in osteosarcoma, the potential of DDR-related genes (DDRGs) remains unclear. Thus, the current research is intended to investigate the mechanisms of DDRGs in the development of osteosarcoma and to explore potential DDR-related biomarkers in forecasting the prognosis of osteosarcoma patients. The osteosarcoma genomic data from TCGA, GEO and cBioPortal databases were utilized for screening and identification of differentially expressed DDRGs (DEDDRGs). Consensus clustering analysis was performed to identify different subtypes of osteosarcoma based on the expressions of DDRGs. Key DEDRRGs were identified by overlapping DEDRRGs between different subtypes and DEDRRGs between tumor and control samples. Univariate, as well as LASSO regressions, were further applied to obtain robust prognostic signatures. GSVA and ssGSEA analysis were implemented to explore the underlying mechanisms of prognostic DDRG signature in regulating osteosarcoma. In addition, the drug sensitivity of patients in low- and high-risk groups was evaluated using pRRophetic algorithm. A total of 43 key DEDRRGs were identified. Followed by univariate Cox along with LASSO regression analyses, CDK6, CSF1R, EGFR, ERBB4, GATA3 and SOCS1 were identified as prognostic signatures in osteosarcoma. Cox regressions revealed that the risk score was an independent prognostic factor in osteosarcoma.  DDR may affect osteosarcoma via regulating immune microenvironment along with influencing cell proliferation, migration, adhesion and apoptosis. The chemotherapeutic response between patients in low- and high-risk groups was much different. The role of DDRGs in osteosarcoma and identified six DDR-linked biomarkers for forecasting the prognosis of osteosarcoma patients. Our outcomes enhanced the understanding of DDR-related molecular mechanisms involved in osteosarcoma and provided potential therapeutic targets for osteosarcoma patients.

Precursor-Directed Biosynthesis of Neoantimycin Derivatives with Selective Cytotoxicity.

A precursor-directed biosynthesis approach led to the accumulation of seven new neoantimycin derivatives (1-7) from Streptomyces conglobatus RJ2. Structure elucidation was conducted using NMR and HRESIMS analysis, and the absolute configuration was determined by advanced Marfey's method, Mosher's analysis, and ECD analysis. The obtained compounds revealed selective and significant cytotoxicity, specifically against colorectal cancer cells bearing the K-ras mutation, with IC50 values ranging from 40 nM to 3.5 µM.

18-Residue Peptaibols Produced by the Sponge-Derived Trichoderma sp. GXIMD 01001.

Seven new 18-residue peptaibols, trichorzins A-G (1-7), were isolated from the sponge-derived fungus Trichoderma sp. GXIMD 01001. Their structures and configurations were characterized by a comprehensive interpretation of the NMR spectroscopic data, MS/MS fragmentation, Marfey's method, and ECD analysis. The general sequences of trichorzins A-G are as follows: Ac-Aib1-Ala/Ser2-Ala3-Aib/Iva4-Iva5-Gln6-Aib/Iva7-Val/allo-Ile8-Aib9-Gly10-Leu11-Aib12-Pro13-Leu14-Aib15-Aib16-Gln17-Trpol/Pheol18. The obtained compounds were assessed for their potential antiproliferative and antimicrobial activities. All obtained compounds did not show potent antibacterial activity but exhibited significant cytotoxicity, with the lowest IC50 values at 0.46-4.7 µM against four human carcinoma cell lines.

An epipolythiodioxopiperazine alkaloid and diversified aromatic polyketides with cytotoxicity from the Beibu Gulf coral-derived fungus Emericella nidulans GXIMD 02509. / 北部湾珊瑚来源构巢裸胞壳菌GXIMD 02509ä¸­å ·æœ‰ç»†èƒžæ¯’æ€§çš„ä¸€ä¸ªå¤šç¡«ä»£äºŒé ®å“Œå—ªç”Ÿç‰©ç¢±å’Œç»“æž„å¤šæ ·çš„èŠ³é¦™èšé ®ç±»åŒ–åˆç‰©.

Marine microorganisms, especially marine fungi, have historically proven their value as a prolific source for structurally novel and pharmacologically active secondary metabolites (Deshmukh et al., 2018; Carroll et al., 2022). The corals constitute a dominant part of reefs with the highest biodiversity, and harbor highly diverse and abundant microbial symbionts in their tissue, skeleton, and mucus layer, with species-specific core members that are spatially partitioned across coral microhabitats (Wang WQ et al., 2022). The coral-associated fungi were very recently found to be vital producers of structurally diverse compounds, terpenes, alkaloids, peptides, aromatics, lactones, and steroids. They demonstrate a wide range of bioactivity such as anticancer, antimicrobial, and antifouling activity (Chen et al., 2022). The genetically powerful genus Emericella (Ascomycota), which has marine and terrestrial sources, includes over 30 species and is distributed worldwide. It is considered a rich source of diverse secondary metabolites with antimicrobial activity or cytotoxicity (Alburae et al., 2020). Notably, Emericella nidulans, the sexual state of a classic biosynthetic strain Aspergillus nidulans, was recently reported as an important source of highly methylated polyketides (Li et al., 2019) and isoindolone-containing meroterpenoids (Zhou et al., 2016) with unusual skeletons.

P38α MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation.

Estrogen and progesterone specify the establishment of uterine receptivity mainly through their respective nuclear receptors, ER and PR. PR is transcriptionally induced by estrogen-ER signaling in the endometrium, but how the protein homeostasis of PR in the endometrium is regulated remains elusive. Here, we demonstrated that the uterine-selective depletion of P38α derails normal uterine receptivity ascribed to the dramatic down-regulation of PR protein and disordered progesterone responsiveness in the uterine stromal compartment, leading to defective implantation and female infertility. Specifically, Ube3c, an HECT family E3 ubiquitin ligase, targets PR for polyubiquitination and thus proteasome degradation in the absence of P38α. Moreover, we discovered that P38α restrains the polyubiquitination activity of Ube3c toward PR by phosphorylating the Ube3c at serine741 . In summary, we provided genetic evidence for the regulation of PR protein stability in the endometrium by P38α and identified Ube3c, whose activity was modulated by P38α-mediated phosphorylation, as an E3 ubiquitin ligase for PR in the uterus.

Penicixanthene E, a new xanthene isolated from a mangrove-derived fungus Penicillium sp.

One new xanthene derivative, named penicixanthene E (1), together with one known compound 2, was isolated from the EtOAc extract of the endophytic fungus Penicillium sp. GXIMD 03101, which was identified from the mangrove Acanthus ilicifolius L. collected in the South China Sea. The structure of 1 was elucidated by 1D and 2D NMR spectral interpretation and HREISMS data. The absolute configurations of C-9 and C-11 in 1 were proposed based on electronic circular dichroism (ECD), but the configuration at C-3 in 1 was unassigned. Compound 1 represents a xanthene derivative that was first reported, in which carbon-carbon double bond has been reduced. The cytotoxic activities of all compounds were evaluated, the result showed that compound 1 has weak activity against pancreatic cancer SW1990.

Phycocyanin Ameliorates Colitis-Associated Colorectal Cancer by Regulating the Gut Microbiota and the IL-17 Signaling Pathway.

Phycocyanin (PC) is a pigment-protein complex. It has been reported that PC exerts anti-colorectal cancer activities, although the underlying mechanism has not been fully elucidated. In the present study, azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mice were orally administrated with PC, followed by microbiota and transcriptomic analyses to investigate the effects of PC on colitis-associated cancer (CAC). Our results indicated that PC ameliorated AOM/DSS induced inflammation. PC treatment significantly reduced the number of colorectal tumors and inhibited proliferation of epithelial cell in CAC mice. Moreover, PC reduced the relative abundance of Firmicutes, Deferribacteres, Proteobacteria and Epsilonbacteraeota at phylum level. Transcriptomic analysis showed that the expression of genes involved in the intestinal barrier were altered upon PC administration, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed the IL-17 signaling pathway was affected by PC treatment. The study demonstrated the protective therapeutic action of PC on CAC.

Integral proteomic analysis of blastocysts reveals key molecular machinery governing embryonic diapause and reactivation for implantation in mice.

Among nearly 100 mammalian species, implantation can be suspended at blastocyst stage for a certain time and reactivated under favorable conditions, a phenomenon known as embryonic diapause. Until now, the underlying molecular mechanism governing embryonic diapause and reactivation for implantation remained largely unknown. Here we conducted the first integral proteomic analysis of blastocysts from diapause to reactivation by using a physiologically relevant mouse delayed implantation model. More than 6000 dormant and reactivated blastocysts were used for the proteomic analysis. A total of 2255 proteins were detected. Various cellular and molecular processes, including protein translation, aerobic glycolysis, pentose phosphate pathway, purine nucleotide biosynthesis, glutathione metabolism, and chromatin organization were identified as differentially regulated. In particular, we demonstrated a remarkable activation of mitochondria in blastocysts upon reactivation from dormancy, highlighting their essential physiological significance. Moreover, the activities of the endosome-lysosome system were prominently enhanced in the mural trophectoderm of reactivated blastocysts, accompanied by active phagocytosis at the fetal-maternal interface, suggesting a critical role in promoting trophoblast invasion. Collectively, we provided an integral proteomic view upon the regulatory network of blastocyst reactivation from diapause, which will help to better interpret the nature of embryonic diapause and reactivation in wild animals and to identify molecular indicators for selecting blastocysts with high implantation competency.