Lei Hu

JOURNAL/nrgr/04.03/01300535-202606000-00067/figure1/v/2026-04-16T195327Z/r/image-tiff Cmyc , a proto-oncogene, is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells. However, recent studies suggest that Cmyc may play a crucial role in maintaining the health and function of mature dopaminergic neurons. This study assessed the role of Cmyc in dopaminergic neurons and its significance in Parkinson’s disease. We used a conditional knockout approach to specifically delete Cmyc in substantia nigra dopaminergic neurons of adult mice. Our findings showed that Cmyc deletion led to progressive neuron loss, Parkinson’s disease-like symptoms, downregulation of Klotho, and upregulation of senescence-associated inflammatory factors, along with enhanced oxidative stress and nitrated alpha-synuclein accumulation, ultimately causing neuronal death. In vitro experiments confirmed increased senescence in C-MYC knockout cells, which was partially reversible by KLOTHO overexpression. We conclude that low-level Cmyc expression is essential for maintaining the health of mature dopaminergic neurons and preventing neurodegeneration, and suggest the c-Myc/Klotho axis as a potential therapeutic target for age-related neurodegenerative diseases, including Parkinson’s disease. Our study introduces a novel mouse model for Parkinson’s disease that replicates a condition associated with normal aging, offering a valuable tool for future research into disease mechanisms and therapeutic strategies.

To combat the SARS-CoV-2 pandemic, innovative prevention strategies are needed, including reducing ACE2 expression on respiratory cells. This study screened approved drugs in China for their ability to downregulate ACE2. Daphnetin (DAP) was found to significantly reduce ACE2 mRNA and protein levels in PC9 cells. DAP exerts its inhibitory effects on ACE2 expression by targeting HIF-1α and JAK2, thereby impeding the transcription of the ACE2 gene. The SARS-CoV-2 pseudovirus infection assay confirmed that DAP-treated PC9 cells exhibited decreased susceptibility to viral infection. At therapeutic doses, DAP effectively lowers ACE2 expression in the respiratory systems of mice and humans. This suggests that DAP, already approved for other conditions, could be a new preventive measure against SARS-CoV-2, offering a cost-effective and accessible way to reduce SARS-CoV-2 spread.

The oncogenic role of Ladinin-1 (LAD1), an anchoring filament protein, is largely unknown. In this study, we conducted a series of studies on the oncogenic role of LAD1 in lung adenocarcinoma (LUAD). Firstly, we analyzed the aberrant expression of LAD1 in LUAD and its correlation with patient survival, tumor immune infiltration, and the activation of cancer signaling pathways. Furthermore, the relationship between LAD1 expression and K-Ras and EGF signaling activation, tumor cell proliferation, migration, and colony formation was studied by gene knockout/knockout methods. We found that LAD1 was frequently overexpressed in LUAD, and high LAD1 expression predicts a poor prognosis. LAD1 exhibits promoter hypomethylation in LUAD, which may contribute to its mRNA upregulation. Single-sample gene set enrichment analysis (ssGSEA) showed that acquired immunity was negatively correlated with LAD1 expression, which was verified by the downregulated GO terms of “Immunoglobulin receptor binding” and “Immunoglobulin complex circulating” in the LAD1 high-expression group through Gene Set Variation Analysis (GSVA). Notably, the Ras-dependent signature was the most activated signaling in the LAD1 high-expression group, and the phosphorylation of downstream effectors, such as ERK and c-jun, was strongly inhibited by LAD1 deficiency. Moreover, we demonstrated that LAD1 depletion significantly inhibited the proliferation, migration, and cell-cycle progression of LUAD cells and promoted sensitivity to Gefitinib, K-Ras inhibitor, and paclitaxel treatments. We also confirmed that LAD1 deficiency remarkably retarded tumor growth in the xenograft model. Conclusively, LAD1 is a critical prognostic biomarker for LUAD and has potential as an intervention target.

Circular RNAs (circRNAs) are novel biomarkers of various cancers. CircRNAs can sponge miRNAs and regulate target mRNAs, which was called competing endogenous RNAs (ceRNA). This study was designed to identify circRNAs related to patients with clear cell renal cell carcinoma (ccRCC) and the first to select three independent Gene Expression Omnibus microarrays covering circRNAs, miRNAs, and mRNAs for multiple analyses. The data of clinical cases applied in our study were obtained from The Cancer Genome Atlas. We successfully conducted a circRNA/miRNA/mRNA ceRNA network related to ccRCC patients via R software and Cytoscape including 8 circRNAs, 6 miRNAs, and 49 mRNAs. The prognosis-associated subnet covered 8 circRNAs, 6 miRNAs, and 22 mRNAs. Quantitative real-time PCR was applied to measure our prediction in three renal cell lines and 23 pairs of tissues. Small interfering RNA targeting the back-splice region of hsa_circ_0001167 was further implied to confirm the regulation. Ultimately, hsa_circ_0001167/hsa-miR-595/CCDC8 regulatory axis was identified in this study, which may serve as prognostic indicators. Lower levels of hsa_circ_0001167 and CCDC8 were potentially correlated with worse patient survival.

Objective The purpose of the article is to establish a quick enrichment and detection method using immunomagnetic beads and flow cytometry to analyze circulating tumor cells (CTCs) in the peripheral blood. Results After incubation with CD326-PE and CD45-APC antibodies, more than 60% MCF7 cells in M-Buffer could be detected while less than 10% of the same cells could be detected by flow cytometry (FCM) if spiked into blood. However, in combination with CD326 and CD45 immunomagnetic beads, detection rate of MCF7 cells in blood reached 57%. For circulating tumor cells, enrichment by CD326 and CD45 immunomagnetic beads improve the detection rate from nearly undetectable to more than 24.14%. Conclusions Live CTCs in peripheral blood can be effectively and sensitively detected by using a combination of immunomagnetic beads (CD45 and CD326) and flow cytometry.

Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.

Glioblastomas (GBM) comprise different subsets that exhibit marked heterogeneity and plasticity, leading to a lack of success of genomic profiling in guiding the development of precision medicine approaches against these tumors. Accordingly, there is an urgent need to investigate the regulatory mechanisms for different GBM subsets and identify novel biomarkers and therapeutic targets relevant in the context of GBM-specific niches. The DHHC family of proteins is associated tightly with the malignant development and progression of gliomas. However, the role of these proteins in the plasticity of GBM subsets remains unclear. This study utilized human glioma proneural or mesenchymal stem cells as indicated. The effects of DHHC proteins on different GBM subsets were investigated through in vitro and in vivo assays (i.e., colony formation assay, flow cytometry assay, double immunofluorescence, western blot, and xenograft model). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to detect the protein complexes of ZDHHC18 and ZDHHC23 in various GBM subtypes, and explore the mechanism of DHHC proteins in targeting different subsets of GSCs in specific niches. ZDHHC18 and ZDHHC23 could target the glioma stem cells of different GBM subsets in the context of their specific niches and regulate the cellular plasticity of these subtypes. Moreover, mechanistic investigations revealed that ZDHHC18 and ZDHHC23 competitively interact with a BMI1 E3 ligase, RNF144A, to regulate the polyubiquitination and accumulation of BMI1. These events contributed to the transition of glioma stem cells in GBM and cell survival under the stressful tumor microenvironment. Our work highlights the role of DHHC proteins in the plasticity of GBM subsets and reveals that BMI1 represents a potential therapeutic target for human gliomas.

The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-β transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

The E. coli phosphomannose isomerase (EcPMI) gene is widely used as a selectable marker gene (SMG) in mannose (Man) selection-based plant transformation. Although some plant species exhibit significant PMI activity and active PMIs were even identified in Man-sensitive plants, whether plant PMIs can be used as SMGs remains unclear. In this study, we isolated four novel PMI genes from Chlorella variabilis and Oryza sativa. Their isoenzymatic activities were examined in vitro and compared with that of EcPMI. The active plant PMIs were separately constructed into binary vectors as SMGs and then transformed into rice via Agrobacterium. In both Indica and Japonica subspecies, our results indicated that the plant PMIs could select and produce transgenic plants in a pattern similar to that of EcPMI. The transgenic plants exhibited an accumulation of plant PMI transcripts and enhancement of the in vivo PMI activity. Furthermore, a gene of interest was successfully transformed into rice using the plant PMIs as SMGs. Thus, novel SMGs for Man selection were isolated from plants and our analysis suggested that PMIs encoding active enzymes might be common in plants and could potentially be used as appropriate genetic elements in cisgenesis engineering.