Construction and validation of prognostic risk model for hepatocellular carcinoma based on biological analysis of palmitoyl-associated enzyme long-chain non-coding RNA

Objective·To explore the effect of screening the expression of long non-coding RNA (lncRNA) related to palmitoylation on prognosis of liver cancer based on The Cancer Genome Atlas (TCGA) database and construct a risk prediction model in liver cancer.Methods·The sequencing data and the corresponding clinical information of 374 liver cancer tissues and 50 normal tissue samples were downloaded from TCGA database. The differential zinc finger aspartate-histidine-histidine-cysteine domain (ZDHHC) between liver cancer tissues and normal tissues was used to construct the expression profile of lncRNA related to ZDHHC. Furthermore, the prediction model was constructed by LASSO regression algorithm and the validity of the model prediction was verified to analyze the relationship between high-risk and low-risk groups and immune function and to predict the response to immunotherapy.Results·There were 20 differentially expressed ZDHHCs in hepatocellular carcinoma, among which 656 lncRNAs were correlated with differential ZDHHCs (all P<0.05). Univariate COX analysis showed that 22 lncRNAs were associated with the prognosis of hepatocellular carcinoma (HR 1.47‒13.05, all P<0.05), and LASSO regression analysis included 3 lncRNAs to construct a risk model. The risk score=0.662 6×AC026356.1+0.213 9×AC026401.3+0.405 6×POLH-AS1. In the model, the overall survival (OS) and progression-free survival (PFS) of patients in the high-risk group were significantly lower than those in the low-risk group (all P<0.05). Multivariate COX regression analysis showed that the model as a risk factor was an independent factor affecting survival (HR=1.375, 95%CI 1.208‒1.566). In the risk model, there were significant differences between high-risk and low-risk immune function pathways, and the response level of high-risk patients to immunotherapy was lower (P<0.05).Conclusion·The use of a risk model based on palm acylation related lncRNA expression can independently predict the survival period of liver cancer patients, providing reference for patients receiving immunotherapy

Mbnl2 loss alters novel context processing and impairs object recognition memory

Summary: Patients with myotonic dystrophy type I (DM1) demonstrate visuospatial dysfunction and impaired performance in tasks requiring recognition or memory of figures and objects. In DM1, CUG expansion RNAs inactivate the muscleblind-like (MBNL) proteins. We show that constitutive Mbnl2 inactivation in Mbnl2ΔE2/ΔE2 mice selectively impairs object recognition memory in the novel object recognition test. When exploring the context of a novel arena in which the objects are later encountered, the Mbnl2ΔE2/ΔE2 dorsal hippocampus responds with a lack of enrichment for learning and memory-related pathways, mounting instead transcriptome alterations predicted to impair growth and neuron viability. In Mbnl2ΔE2/ΔE2 mice, saturation effects may prevent deployment of a functionally relevant transcriptome response during novel context exploration. Post-novel context exploration alterations in genes implicated in tauopathy and dementia are observed in the Mbnl2ΔE2/ΔE2 dorsal hippocampus. Thus, MBNL2 inactivation in patients with DM1 may alter novel context processing in the dorsal hippocampus and impair object recognition memory

Cardiac CaMKIIδ and Wenxin Keli Prevents Ang II-Induced Cardiomyocyte Hypertrophy by Modulating CnA-NFATc4 and Inflammatory Signaling Pathways in H9c2 Cells

Previous studies have demonstrated that calcium-/calmodulin-dependent protein kinase II (CaMKII) and calcineurin A-nuclear factor of activated T-cell (CnA-NFAT) signaling pathways play key roles in cardiac hypertrophy (CH). However, the interaction between CaMKII and CnA-NFAT signaling remains unclear. H9c2 cells were cultured and treated with angiotensin II (Ang II) with or without silenced CaMKIIδ (siCaMKII) and cyclosporine A (CsA, a calcineurin inhibitor) and subsequently treated with Wenxin Keli (WXKL). Patch clamp recording was conducted to assess L-type Ca2+ current (ICa-L), and the expression of proteins involved in signaling pathways was measured by western blotting. Myocardial cytoskeletal protein and nuclear translocation of target proteins were assessed by immunofluorescence. The results indicated that siCaMKII suppressed Ang II-induced CH, as evidenced by reduced cell surface area and ICa-L. Notably, siCaMKII inhibited Ang II-induced activation of CnA and NFATc4 nuclear transfer. Inflammatory signaling was inhibited by siCaMKII and WXKL. Interestingly, CsA inhibited CnA-NFAT pathway expression but activated CaMKII signaling. In conclusion, siCaMKII may improve CH, possibly by blocking CnA-NFAT and MyD88 signaling, and WXKL has a similar effect. These data suggest that inhibiting CaMKII, but not CnA, may be a promising approach to attenuate CH and arrhythmia progression