Nicotinamide N-methyltransferase (NNMT) is overexpressed in various human tumors and involved in the development and progression of several carcinomas. In breast cancer, NNMT was found to be overexpressed in several cell lines. However, the clinical relevance of NNMT in breast cancer is not yet clear.NNMT expression in breast carcinoma was examined by immunohistochemistry, and then, its relationship with patient clinicopathological characteristics was analyzed. The effects of NNMT on chemoresistance in breast cancer cells were assessed by cell viability, colony formation, and apoptosis assay. The NNMT, SIRT1, p53, and acetyl-p53 proteins, which are involved in NNMT-related chemoresistance, were examined by Western blotting. The SIRT1 mRNA was examined by real-time PCR, and its activity was measured by using the SIRT1 deacetylase fluorometric reagent kit.NNMT expression was significantly higher (53.9%) in breast carcinoma than in paracancerous tissues (10.0%) and breast hyperplasia (13.3%). A high level of NNMT expression correlated with poor survival and chemotherapy response in breast cancer patients who received chemotherapy. Ectopic overexpression of NNMT significantly inhibited the apoptotic cell death and suppression of colony formation induced by adriamycin and paclitaxel. Mechanistic studies revealed that NNMT overexpression increased SIRT1 expression and promoted its activity. Either inhibition of SIRT1 by EX527 or knockdown of SIRT1 by siRNA could reverse NNMT-mediated resistance to adriamycin and paclitaxel, which suggests that SIRT1 plays a critical role in NNMT-related chemoresistance in breast cancer.The results of this study demonstrate a novel correlation between the NNMT expression level and patient survival, suggesting that NNMT has the potential to become a new prognostic biomarker to predict the treatment outcomes of the clinical chemotherapy in breast cancer. Moreover, targeting NNMT or downstream SIRT1 may represent a new therapeutic approach to improve the efficacy of breast cancer chemotherapy.
The predatory natural enemy Eocanthecona furcellata plays a crucial role in agricultural ecosystems due to its effective pest control measures and defensive venom. Predator venom contains serine protease inhibitors (SPIs), which are the primary regulators of serine protease activity and play key roles in digestion, development, innate immunity, and other physiological regulatory processes. However, the regulation mechanism of SPIs in the salivary glands of predatory natural enemies is still unknown. In this study, we sequenced the transcriptome of E. furcellata salivary gland and identified 38 SPIs genes named EfSPI1∼EfSPI38 . Through gene structure, multiple sequence alignment and phylogenetic tree analysis, real-time quantitative PCR (RT-PCR) expression profiles of different developmental stages and different tissues were analyzed. RNAi technology was used to explore the gene function of EFSPI20 . The results showed that these 38 EfSPIs genes contained 8 SPI domains, which were serpin, TIL, Kunitz, Kazal, Antistasin, Pacifastin, WAP and A2M. The expression profile results showed that the expression of different types of EfSPIs genes was different at different developmental stages and different tissues. Most of the EfSPIs genes were highly expressed in the egg stage. The EfSPI20, EfSPI21, EfSPI22 , and EfSPI24 genes of the Pacifastin subfamily and the EfSPI35 gene of the A2M subfamily were highly expressed in the nymphal and adult stages, which was consistent with the RT-qPCR verification results. These five genes are positively correlated with each other and have a synergistic effect on E. furcellata , and they were highly expressed in salivary glands. After interfering with the expression of the EfSPI20 gene, the survival rate and predatory amount of male and female adults were significantly decreased. Taken together, we speculated some EfSPIs may inhibit trypsin, chymotrypsin, and elastase, and some EfSPIs may be involved in autoimmune responses. EfSPI20 was essential for the predation and digestion of E. furcellata , and the functions of other EfSPIs were discussed. Our findings provide valuable insights into the diversity of EfSPIs in E. furcellata and the potential functions of regulating their predation, digestion and innate immunity, which may be of great significance for developing new pest control strategies.
Bladder cancer, a prevalent malignant neoplasm of the urinary tract, exhibits escalating morbidity and mortality rates.Current diagnosis standards rely on invasive and costly cystoscopy and histopathology, underscoring the urgency for non-invasive, high-throughput, and cost-effective novel diagnostic techniques to ensure timely detection and standardized treatment.Recent years have witnessed the rise of exosome research in bladder cancer studies.Exosomes contain abundant bioactive molecules that can help elucidate the intricate mechanisms underlying bladder cancer pathogenesis and metastasis.Exosomes hold potential as biomarkers for early bladder cancer diagnosis while also serving as targeted drug delivery vehicles to enhance treatment efficacy and mitigate adverse effects.Furthermore, exosome analyses offer insights into the complex molecular signaling networks implicated in bladder cancer progression, revealing novel therapeutic targets.This review provides a comprehensive overview of prevalent exosome isolation techniques and highlights the promising clinical utility of exosomes in both diagnostic and therapeutic applications in bladder cancer management.
Abstract Gram-negative sepsis has become one of major increasing medical burdens globally, which is subjected to growing antibiotic resistance problem and the relatively delayed development of new antibiotics. LL-37, the only type of Cathelicidin identified in humans, has diverse biological activities including direct bactericidal action, regulation of inflammation and LPS-neutralization. The KR-12 peptide is the smallest portion of LL-37 with antibacterial action, which has been shown that could be modified into more effective antimicrobials. Here, we synthesize two myristoylated derivatives of KR-12, Myr-KR-12N and Myr-KR-12C, which can spontaneously form nanoparticles when mixed with deionized water. We show that myristoylated KR-12 derivatives possess a broad-spectrum and more powerful bactericidal activity through interrupting the membranes of bacteria. Myr-KR-12N rescues mice from lethal sepsis induced by E. coli , even more potent rescuing activity than meropenem. We also demonstrate that myristoylated KR-12 nanobiotic can significantly bind with LPS and inhibit the inflammation in vitro and Myr-KR-12N rescue mice from LPS-induced sepsis in vivo , even more potent rescuing activity than polymyxin B. Toxic experiments indicate that neither Myr-KR-12N nor Myr-KR-12C nanobiotics exhibits meaningful hemolytic activity, liver and kidney injury. We thus developed a novel nanobiotic with dual bactericidal and LPS-neutralization properties, which may provide good insights for clinical translation of antimicrobial peptides and the creation of new antibiotics.
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