Melatonin has been indicated to ameliorate tau hyperphosphorylation in the pathogenesis of tau diseases, but the role of melatonin-receptor signal transduction has not been clearly discovered. In this study, we found intensive tau hyperphosphorylation in melatonin receptor knockout mice. Bielschowsky silver staining showed ghostlike neurofibrillary tangles in melatonin receptor-2 knockout (MT2KO) as well as melatonin receptors-1 and -2 knockout (DKO) mice, and an argyrophilic substance was deposited in melatonin receptor-1 knockout (MT1KO) mice. Furthermore, we found significantly decreased activity of protein phosphatase 2A (PP2A) by Western blot and enzyme-linked immunosorbent assay (ELISA), which was partly due to the overexpression of protein phosphatase methylesterase-1 (PME-1), but not glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5) or protein kinase B (Akt). Finally, we observed a significant increase in cyclic adenosine monophosphate (cAMP) and a decrease in miR-125b-5p levels in MT1KO, MT2KO and DKO mice. Using a luciferase reporter assay, we discovered that miR-125b-5p largely decreased the expression of firefly luciferase by interfering with the 3′UTR of PME-1. Furthermore, miR-125b-5p mimics significantly decreased the expression of PME-1, while miR-125b-5p inhibitor induced tau hyperphosphorylation. These results show that melatonin-receptor signal transduction plays an important role in tau hyperphosphorylation and tangle formation.

Introduction: WD Repeat Domain Phosphoinositide Interacting 2 (WIPI2) is a WD repeat protein that interacts with phosphatidylinositol and regulates multiprotein complexes by providing a b-propeller platform for synchronous and reversible protein-protein interactions assembled proteins. Ferroptosis is a novel iron-dependent form of cell death. It is usually accompanied with the accumulation of membrane lipid peroxides. Our study is to focus on investigating the effect of WIPI2 on the growth and ferroptosis of colorectal cancer (CRC) cells and its potential mechanism.Methods: We analyzed the expression of WIPI2 in colorectal cancer versus normal tissues through The Cancer Genome Atlas (TCGA), and the relationship between clinical traits and WIPI2 expression and prognosis was assessed by univariate and multifactorial cox analysis. Next, we constructed the siRNAs targeting the WIPI2 sequence si-WIPI2 to further investigate the mechanism of WIPI2 in CRC cells through vitro experiments.Results: Public data from the TCGA platform showed that WIPI2 expression was significantly elevated in colorectal cancer tissues compared to paracancerous tissues, and high WIPI2 expressionpredicted poor prognosis for CRC patients. Moreover, we found that the knockdown of WIPI2 expression could inhibit the growth and proliferation of HCT116 and HT29 cells. Furthermore, we found that the expression level of ACSL4 decreased and that of GPX4 increased when WIPI2 was knocked down, suggesting that WIPI2 can potentially positively regulate CRC ferroptosis. Meanwhile, both NC and si groups were able to further inhibit cell growth activity, as well as increase WIPI2 and decrease GPX4 expression when treated with Erastin, but the rate of cell viability inhibition and the trend of protein changes were more significantly in the NC group than si groups, which indicated that Erastin induced CRC ferroptosis through the WIPI2/GPX4 pathway thereby enhancing the sensitivity of colorectal cancer cells to Erastin.Conclusions: Our study suggested that WIPI2 had a promotional effect on the growth of colorectal cancer cells, and it also played an important role in the ferroptosis pathway.

Alzheimer’s disease (AD) was characterized by the presence of neurofibrillary tangles and senile plaques. Although melatonin plays an important role in AD, its mechanism is still unknown. In this study, we found obvious cognition damage in melatonin receptor 2 knockout mice (MT2KO) and double knockout mice (DKO), but not in melatonin receptor 1 knockout mice (MT1KO). To explore the mechanism in-depth, we attempted to determine the levels of metabolites and amyloid-β peptide (Aβ). A high level of Cho/tCr (choline/total creatine) was detected in MT2KO and MT1KO by nuclear magnetic resonance (NMR), while a high level of myo-inositol/total creatine (mI/tCr) was only detected in MT1KO. A higher ratio of Aβ42/40 was found in MT2KO, but not in MT1KO and DKO. We also found an abnormal increase of plaque detected by the A3981 antibody in MT2KO and DKO. Furthermore, a huge decrease of postsynapses was confirmed in MT2KO and DKO, but not MT1KO, accompanied by a low level of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) at the site of serine 133 and a low activity of protein kinase A. Finally, the cAMP, cyclic guanosine monophosphate, and cAMP-regulated guanine nucleotide exchange factor (EPAC) were detected. We observed a significant decrease of cAMP and EPAC2 in MT2KO, but not MT1KO. Thus, we identified that cAMP-related signaling pathway was disturbed in MT2KO and was critical for normal cognitive function.

Introduction: Although many studies have demonstrated the existing neurological symptoms in COVID-19 patients, the mechanisms are not clear until now. This study aimed to figure out the critical molecular and immune infiltration situations in the brain of elderly COVID-19 patients.Methods: GSE188847 was used for the differential analysis, WGCNA, and immune infiltration analysis. We also performed GO, KEGG, GSEA, and GSVA for the enrich analysis.Results: 266 DEGs, obtained from the brain samples of COVID-19 and non-COVID-19 patients whose ages were over 70 years old, were identified. GO and KEGG analysis revealed the enrichment in synapse and neuroactive ligand-receptor interaction in COVID-19 patients. Further analysis found that asthma and immune system signal pathways were significant changes based on GSEA and GSVA. Immune infiltration analysis demonstrated the imbalance of CD8+ T cells, neutrophils, and HLA. The MEpurple module genes were the most significantly different relative to COVID-19. Finally, RPS29, S100A10, and TIMP1 were the critical genes attributed to the progress of brain damage.Conclusion: RPS29, S100A10, and TIMP1 were the critical genes in the brain pathology of COVID-19 in elderly patients. Our research has revealed a new mechanism and a potential therapeutic target.

Knee osteoarthritis (KOA) is one of the most common degenerative joint diseases in the elderly worldwide. The primary lesion in patients with KOA is the degeneration of articular cartilage. This study aimed to observe the biological effects of cyclic negative pressure on C28/I2 chondrocytes and to elucidate the underlying molecular mechanisms. We designed a bi-directional intelligent micro-pressure control device for cyclic negative pressure intervention on C28/I2 chondrocytes. Chondrocyte vitality and proliferation were assessed using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. The extracellular matrix was analyzed using real-time fluorescence quantitative polymerase chain reaction (PCR) and western blot, while the molecular mechanism of the chondrocyte response to cyclic negative pressure was explored through mRNA sequencing. Experimental data demonstrated that cyclic negative pressure promoted chondrocyte proliferation and upregulated the expression of chondrocyte-specific protein, namely the collagen type II alpha 1 chain (COL2A1) protein, and the transcription factor SRY-box transcription factor 9 (SOX9). Additionally, RNA sequencing analysis revealed that the gene levels of insulin-like growth factor 2 (IGF-2) and early growth response 1 (EGR-1) were significantly elevated in the cyclic negative pressure group. This study demonstrates that cyclic negative pressure stimulates the proliferation of C28/I2 chondrocytes by promoting the expression of EGR-1 and IGF-2. This new discovery may provide novel insights into cartilage health and KOA prevention.

RNA editing is recognized as a crucial factor in cancer biology. Its potential application in predicting the prognosis of colon adenocarcinoma (COAD) remains unexplored. RNA editing data of COAD patients were downloaded from the Synapse database. LASSO regression was used to construct the risk model and verified by the receiver operating characteristic (ROC) curve. GO and KEGG enrichment analyses were performed to delineate the biological significance of the differentially expressed genes. Finally, differential analysis and immunohistochemistry were used to verify the expression of adenosine deaminase 1 (ADAR1). We evaluated a total of 4079 RNA editing sites in 514 COAD patients from Synapse database. A prognostic signature was constructed based on five genes were significantly associated with the prognosis of COAD patients including GNL3L, NUP43, MAGT1, EMP2, and ARSD. Univariate and multivariate Cox regression analysis revealed that RNA editing-related genes (RERGs)-related signature was an independent risk factor for COAD. Moreover, Experimental evidence shows that ADAR1 is highly expressed in colon adenocarcinoma and silencing ADAR1 can inhibit cancer cell proliferation. We established a prognostic model based on five RERGs with strong predictive value. This model not only serves as a foundation for a novel prognostic tool but also facilitates the identification of potential drug candidates for treating COAD.