Colon cancer (CC) is one of the major malignancies worldwide, whose pathogenesis is complex and requires the accumulated alteration of multiple genes and signaling pathways. Condensins are multi-protein complexes that play pivotal roles in chromosome assembly and segregation during mitosis, meiosis and even tumorigenesis. Using tissue microarrays by immunohistochemistry and hematoxylin–eosin staining, we found that non-SMC condensin I complex subunit H (NCAPH) in colon cancerous tissues was higher than that in all corresponding adjacent non-cancerous tissues. We then characterized the exact function of the NCAPH in CC. We provided evidences showing that NCAPH is highly expressed in colorectal cancer cell lines comparing with normal human colonic epithelial cells, and identified many NCAPH mutations in CC patients. We found that depletion of NCAPH inhibits CC cell proliferation, migration in vitro and xenograft tumor formation in vivo. Furthermore, NCAPH knockdown promotes cell apoptosis and cell cycle arrest at G2/M phase. Interestingly, the NCAPH high expression in tumor tissues of colon patients had a significantly better prognosis and survival rate than low-expression patients, suggesting that NCAPH high expression promotes colonic cancerous cell proliferation; on the other hand, it may also sensitize these cells responding to chemo- or radio-therapies. Collectively, these findings reveal an important role of NCAPH in CC, indicating that NCAPH could be used as a new therapeutic target in future.
Limited circulating tumor cells (CTCs) capturing efficiency and lack of regulation capability on CTC-supportive metastatic niches (MNs) are two main obstacles hampering the clinical translation of conventional liposomes for the treatment of metastatic breast cancers. Traditional delivery strategies, such as ligand modification and immune modulator co-encapsulation for nanocarriers, are inefficient and laborious. Here, a multifunctional Rg3 liposome loading with docetaxel (Rg3-Lp/DTX) was developed, in which Rg3 was proved to intersperse in the phospholipid bilayer and exposed its glycosyl on the liposome surface. Therefore, it exhibited much higher CTC-capturing efficiency via interaction with glucose transporter 1 (Glut1) overexpressed on CTCs. After reaching the lungs with CTCs, Rg3 inhibited the formation of MNs by reversing the immunosuppressive microenvironment. Together, Rg3-Lp/DTX exhibited excellent metastasis inhibition capacity by CTC (“seeds”) neutralization and MN (“soil”) inhibition. The strategy has great clinical translation prospects for antimetastasis treatment with enhanced therapeutic efficacy and simple preparation process.
Intrauterine adhesions (IUAs) have caused serious harm to women’s reproductive health. Although emerging evidence has linked intrauterine microbiome to gynecological diseases, the association of intrauterine microbiome with IUA, remains unknown. We performed metagenome-wide association, metabolomics, and transcriptomics studies on IUA and non-IUA uteri of adult rats to identify IUA-associated microbial species, which affected uterine metabolites and endometrial transcriptions. A rat model was used with one side of the duplex uterus undergoing IUA and the other remaining as a non-IUA control. Both 16S rRNA sequencing and metagenome-wide association analysis revealed that instead of Mycoplasmopsis specie in genital tract, murine lung pathogen Mycoplasmopsis pulmonis markedly increased in IUA samples and displayed a distinct positive interaction with the host immune system. Moreover, most of the IUA-enriched 58 metabolites positively correlate with M. pulmonis, which inversely correlates with a mitotic progression inhibitor named 3-hydroxycapric acid. A comparison of metabolic profiles of intrauterine flushing fluids from human patients with IUA, endometritis, and fallopian tube obstruction suggested that rat IUA shared much similarity to human IUA. The endometrial gene Tenascin-N, which is responsible for extracellular matrix of wounds, was highly up-regulated, while the key genes encoding parvalbumin, trophectoderm Dkkl1 and telomerase involved in leydig cells, trophectoderm cells, activated T cells and monocytes were dramatically down-regulated in rat IUA endometria. Treatment for rat IUA with estrogen (E2), oxytetracycline (OTC), and a traditional Chinese patent medicine GongXueNing (GXN) did not reduce the incidence of IUA, though inflammatory factor IL-6 was dramatically down-regulated (96–86%) with all three. Instead, in both the E2 and OTC treated groups, IUA became worse with a highly up-regulated B cell receptor signaling pathway, which may be associated with the significantly increased proportions of Ulvibacter or Staphylococcus. Our results suggest an association between intrauterine microbiota alterations, certain uterine metabolites, characteristic changes in endometrial transcription, and IUA and the possibility to intervene in IUA formation by targeting the causal factors, microbial infection, and Tenascin-like proteins.
Sesquiterpenyl epoxy-cyclohexenoids (SECs) that depend on a polyketide synthase−terpenoid synthase (PKS−TPS) pathway are widely distributed in plant pathogenic fungi. However, the biosynthesis and function of the acetylated SECs still remained cryptic. Here, we identified that AOL_s00215g 273 (273) was responsible for the acetylation of SECs in Arthrobotrys oligospora via the construction of Δ273, in which the acetylated SECs were absent and major antibacterial nonacetylated SECs accumulated. Mutant Δ273 displayed increased trap formation, and nematicidal and antibacterial activities but decreased fungal growth and soil colonization. Glutamine, a key precursor for NH 3 as a trap inducer, was highly accumulated, and biologically active phenylpropanoids and antibiotics were highly enriched in Δ273. The decreased endocytosis and increased autophagosomes, with the most upregulated genes involved in maintaining DNA and transcriptional stability and pathways related to coronavirus disease and exosome, suggested that lack of 273 might result in increased virus infection and the acetylation of SECs played a key role in fungal diverse antagonistic ability.
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