NNMT/1-MNA Promote Cell-Cycle Progression of Breast Cancer by Targeting UBC12/Cullin-1-Mediated Degradation of P27 Proteins.

Cell cycle dysregulation is a defining feature of breast cancer. Here, 1-methyl-nicotinamide (1-MNA), metabolite of nicotinamide N-methyltransferase(NNMT) is identified, as a novel driver of cell-cycle progression in breast cancer. NNMT, highly expressed in breast cancer tissues, positively correlates with tumor grade, TNM stage, Ki-67 index, and tumor size. Ablation of NNMT expression dramatically suppresses cell proliferation and causes cell-cycle arrest in G0/G1 phase. This phenomenon predominantly stems from the targeted action of 1-MNA, resulting in a specific down-regulation of p27 protein expression. Mechanistically, 1-MNA expedites the degradation of p27 proteins by enhancing cullin-1 neddylation, crucial for the activation of Cullin-1-RING E3 ubiquitin ligase(CRL1)-an E3 ubiquitin ligase targeting p27 proteins.  NNMT/1-MNA specifically up-regulates the expression of UBC12, an E2 NEDD8-conjugating enzyme required for cullin-1 neddylation. 1-MNA showes high binding affinity to UBC12, extending the half-life of UBC12 proteins via preventing their localization to lysosome for degradation. Therefore, 1-MNA is a bioactive metabolite that promotes breast cancer progression by reinforcing neddylation pathway-mediated p27 degradation. The study unveils the link between NNMT enzymatic activity with cell-cycle progression, indicating that 1-MNA may be involved in the remodeling of tumor microenvironment.

The Expression Characteristics and Function of the RECQ Family in Pan-Cancer.

BACKGROUND: The genes of the RECQ DNA helicase family play a part in preserving the stability of the genome and controlling different disease mechanisms. However, the expression features of RECQs in relation to pan-cancer, their correlation with the immune microenvironment of tumors, and the landscape of prognostic power are still undisclosed. METHODS: Various sequence and clinical data extracted from 33 cancers were utilized to generate a comprehensive overview of RECQs in the landscape. Afterward, we discovered variations in gene expression, potential enrichment of functions, genetic alterations, and analysis related to the immune response in tumors. Additionally, we explored the clinical characteristics and diagnostic significance of RECQs. And the important association of RECQL4 with liver hepatocellular carcinoma (LIHC) was investigated. RESULTS: RECQs exhibited extensive mutations in different types of cancers. The expression of RECQ may be influenced by an oncogenic mutation in certain types of cancer, resulting in the observed genomic and epigenetic changes in diverse tumor formations. Furthermore, RECQs originating from tumors exhibited a significant association with the immune microenvironment of the tumor, indicating their potential as promising targets for therapy. Patient prognosis was significantly associated with the majority of genes in the RECQ family. In LIHC, RECQL4 eventually emerged as a separate prognostic determinant. CONCLUSIONS: To summarize, RECQs are essential for the regulation of the immune system in tumors, and RECQL4 serves as a prognostic indicator in LIHC. The results of our study offer fresh perspectives on RECQs from a bioinformatics perspective and emphasize the importance of RECQs in the diagnosis and treatment of cancer.

Antimicrobial Peptides and Cell-Penetrating Peptides: Non-Antibiotic Membrane-Targeting Strategies Against Bacterial Infections.

The prevalence of antimicrobial resistance (AMR) has been rising quickly in recent years. AMR has emerged as a significant obstacle to the treatment of infectious diseases, and many attempts have been made over the past decades to find the best antimicrobials to overcome it. Therefore, it is crucial to find new medicines to combat the global rise of AMR. Antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), which target membranes, are promising antibiotic substitutes. AMPs and CPPs are short amino acid sequences with antibacterial activity as well as possible therapeutic benefits. In this review, we provide a thorough and systematic introduction to the advancement of research on AMPs and CPPs, including information on their classification, mechanism of action, current state of application, limitations and optimization.

Nanotechnology-based diagnostic methods for coronavirus: From nucleic acid extraction to amplification.

The recent emergence of human coronaviruses (CoVs) causing severe acute respiratory syndrome (SARS) is posing a great threat to global public health. Therefore, the rapid and accurate identification of pathogenic viruses plays a vital role in selecting appropriate treatments, saving people's lives and preventing epidemics. Nucleic acids, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), are natural biopolymers composed of nucleotides that store, transmit, and express genetic information. Applications of nucleic acid detection range from genotyping and genetic prognostics, to expression profiling and detection of infectious disease. The nucleic acid detection for infectious diseases is widely used, as evidenced by the widespread use of COVID-19 tests for the containment of the pandemic. Nanotechnology influences all medical disciplines and has been considered as an essential tool for novel diagnostics, nanotherapeutics, vaccines, medical imaging, and the utilization of biomaterials for regenerative medicine. In this review, the recent advances in the development of nanotechnology-based diagnostic methods for coronavirus, and their applications in nucleic acid detection are discussed in detail. The techniques for the amplification of nucleic acids are summarized, as well as the use of magnetic nanoparticles for nucleic acid extraction. Besides, current challenges and future prospects are proposed, along with the great potential of nanotechnology for the effective diagnosis of coronavirus.

Nicotinamide N-methyltransferase inhibits autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells.

BACKGROUND: Nicotinamide N-methyltransferase (NNMT) is highly expressed in several cancers and can regulate cell epigenetic status and various cell metabolism pathways, such as ATP synthesis and cellular stress response. We reported in our previous papers that NNMT overexpression inhibits the apoptosis and enhances the chemotherapy resistance of breast cancer cells. This study aims to investigate the effect of NNMT on autophagy induced by oxidative stress in breast cancer cells, which might provide a novel therapeutic strategy for breast cancer treatment. METHODS: NNMT and LC3B II protein levels in the two cell models (SK-BR-3 and MDA-MB-231) with NNMT overexpression or knockdown were detected by Western blotting and correlated with each other. Changes in cellular viability, intracellular reactive oxygen species (ROS) and ATP levels were assessed after H2O2 treatment. Then, autophagosomes were imaged by transmission electron microscopy, and LC3 puncta were examined by confocal microscopy and flow cytometry. The LC3B II level and AMPK-ULK1 pathway activity were both detected by Western blotting to determine the role of NNMT in the H2O2-induced autophagy. RESULTS: NNMT expression was negatively correlated with LC3B II expression in both cell models (SK-BR-3 and MDA-MB-231). Then, NNMT overexpression attenuated the autophagy induced by H2O2 in SK-BR-3 cells, whereas knockdown promoted autophagy induced by H2O2 in MDA-MB-231 cells. Furthermore, mechanistic studies showed that NNMT suppressed the ROS increase, ATP decrease and AMPK-ULK1 pathway activation, resulting in the inhibition of H2O2-induced autophagy in breast cancer cells. CONCLUSIONS: We conclude that NNMT inhibits the autophagy induced by oxidative stress through the ROS-mediated AMPK-ULK1 pathway in breast cancer cells and may protect breast cancer cells against oxidative stress through autophagy suppression.

Ureaplasma spp. lipid-associated membrane proteins induce human monocyte U937 cell cycle arrest through p53-independent p21 pathway.

Ureaplasma spp. are known to be associated with human genitourinary tract diseases and perinatal diseases and Ureaplasma spp. Lipid-associated membrane proteins (LAMPs) play important roles in their related diseases. However, the exact mechanism underlying pathogenesis of Ureaplasma spp. LAMPs is largely unknown. In this study, we explored the pathogenic mechanisms of Ureaplasma spp. LAMPs by elucidating their role in modulating the cell cycle and related signaling pathways in human monocytic cell U937, which is highly related to the inflammatory and protective effect in infectious diseases. We utilized the two ATCC reference strains (Ureaplasma parvum serovar 3 str. ATCC 27,815 (UPA3) and Ureaplasma urealyticum serovar 8 str. ATCC 27,618 (UUR8)) and nine clinical isolates which including both UPA and UUR to study the effects of Ureaplasma spp. LAMPs on U937 in vitro. We found that LAMPs derived from UUR8 and both UPA and UUR of clinical strains markedly inhibited the cell proliferation, while UPA3 LAMPs suppressed slightly. Besides, the result of flow cytometry analysis indicated all the Ureaplasma spp. LAMPs could arrest U937 cells in G1 phase. Next, we found that the cell cycle arrest was associated with increased levels of p53 and p21, and a concomitant decrease in the levels of CDK2, CDK4, CDK6 and cyclin E1 at both transcriptional and translational levels after treatment with LAMPs derived from UUR8 or clinical strains, while only cyclin E1 was down-regulated after treatment with UPA3 LAMPs. Further study showed that p53 down-regulation had almost no effect on the distribution of cell cycle and the expression of p21. In conclusion, this study demonstrated that LAMPs derived from UUR8 and clinical strains could inhibit the proliferation of U937 cells by inducing G1 cell cycle arrest through increasing the p21 expression in a p53-independent manner, while UPA3 LAMPs could induce the cell cycle arrest slightly. Our study could contribute to the understanding of Ureaplasma spp. pathogenesis, which has potential value for the treatment of Ureaplasma spp. infections.

Delineating the underlying molecular mechanisms and key genes involved in metastasis of colorectal cancer via bioinformatics analysis.

Colorectal cancer (CRC) is considered the world's fourth most deadly cancer. Its metastasis is associated with poor prognosis and weakens the effects of treatment. However, the potential molecular mechanisms and key genes involved in CRC metastasis have remained to be comprehensively elucidated. The objective of the present study was to identify the key genes and molecular pathways underlying CRC metastasis. Differentially expressed genes (DEGs) between primary CRC tissues and metastatic CRC were identified by analyzing the GSE2509 dataset from the Gene Expression Omnibus database. Subsequently, the DEGs were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses via the Database for Annotation, Visualization and Integrated Discovery (DAVID). Next, the top ten hub genes were identified in a protein-protein interaction (PPI) network. Sub-network and pathway enrichment analysis were respectively performed with the plugin MCODE and DAVID. Finally, reverse transcription-quantitative polymerase chain reaction assays were performed to corroborate the expression levels of the top five potential metastasis-associated genes in the clinical samples of CRC patients. A total of 7,384 DEGs were obtained, among which 3,949 were upregulated and 3,435 were downregulated. GO and KEGG enrichment analyses identified numerous possible biological processes and pathways that may have a role in the metastasis of CRC. The leading ten hub genes, recognized from the PPI, were epidermal growth factor receptor (EGFR), Has proto-oncogene GTPase (HRas), Wnt family member 5A (Wnt5a), serine/threonine kinase 1 (Akt1), cyclin-dependent kinase inhibitor 1A (CDKN1a), early growth response 1, Ras homolog family member A, cyclin D1 and Ras-related C3 botulinum toxin substrate 1. Sub-network analysis disclosed the most prominent three modules. Ultimately, EGFR, HRas and Akt1 were verified to be upregulated DEGs, while Wnt5a and CDKN1a were downregulated DEGs when compared with the primary controls. In conclusion, the present study revealed several key genes and relevant molecular mechanisms that may enhance the current understanding of CRC metastasis, making them significant potential foci for the discovery of further CRC treatments.