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Single-cell dissection, hdWGCNA and deep learning reveal the role of oxidatively stressed plasma cells in ulcerative colitis.

Ulcerative colitis (UC) develops as a result of complex interactions between various cell types in the mucosal microenvironment. In this study, we aim to elucidate the pathogenesis of ulcerative colitis at the single-cell level and unveil its clinical significance. Using single-cell RNA sequencing and high-dimensional weighted gene co-expression network analysis, we identify a subpopulation of plasma cells (PCs) with significantly increased infiltration in UC colonic mucosa, characterized by pronounced oxidative stress. Combining 10 machine learning approaches, we find that the PC oxidative stress genes accurately distinguish diseased mucosa from normal mucosa (independent external testing AUC=0.991, sensitivity=0.986, specificity=0.909). Using MCPcounter and non-negative matrix factorization, we identify the association between PC oxidative stress genes and immune cell infiltration as well as patient heterogeneity. Spatial transcriptome data is used to verify the infiltration of oxidatively stressed PCs in colitis. Finally, we develop a gene-immune convolutional neural network deep learning model to diagnose UC mucosa in different cohorts (independent external testing AUC=0.984, sensitivity=95.9%, specificity=100%). Our work sheds light on the key pathogenic cell subpopulations in UC and is essential for the development of future clinical disease diagnostic tools.

A novel ferroptosis-related microRNA signature with prognostic value in osteosarcoma.

The induction of ferroptosis is suggested to be a potential therapeutic strategy for cancers. MicroRNAs (miRNAs) are reported to play an important role in cell death processes. This study aims to construct and validate a risk model based on ferroptosis-related miRNAs (FR_miRNAs) to predict prognosis and identify novel therapeutic targets for osteosarcoma. Data from the Therapeutically Applicable Research to Generate Effective Treatments database are used as the training cohort. A prognostic signature based on two FR_miRNAs (miR-635 and miR-593) is developed using univariate Cox regression, least absolute shrinkage and selection operator regression, and multivariate Cox regression analyses. The area under the curve values of the prognostic signature to predict the 1-year, 2-year, 3-year, and 5-year overall survival rates in patients with osteosarcoma are 0.782, 0.781, 0.722, and 0.777, respectively, indicating a good predictive ability. Based on the risk score, patients are divided into low-risk and high-risk groups. Patients with high-risk scores are associated with poor survival. The risk level is determined to be an independent prognostic factor. A nomogram is established for predicting prognosis. The expression levels of PRNP (miR-635-related ferroptosis-related gene (FRG); P=0.024) and HILPDA (miR-593-related FRG; P=0.025) are significantly different between the low-risk and high-risk groups. All results are validated in an external cohort (GSE39040). The results of the functional assay reveal that miR-635 mimics inhibit osteosarcoma (OS) cell proliferation and migration, whereas miR-593 overexpression exerts the opposite effect. In conclusion, miR-635 and miR-593 exert contrasting regulatory effects on OS cell proliferation and migration.

PHD3 inhibits colon cancer cell metastasis through the occludin-p38 pathway.

Prolyl hydroxylase 3 (PHD3) hydroxylates HIFα in the presence of oxygen, leading to HIFα degradation. PHD3 inhibits tumorigenesis. However, the underlying mechanism is not well understood. Herein, we demonstrate that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 MAPK pathway independent of its hydroxylase activity. We find that PHD3 inhibits colon cancer cell metastasis in the presence of the PHD inhibitor DMOG, and prolyl hydroxylase-deficient PHD3 (H196A) suppresses cell metastasis as well. PHD3 controls the stability of the tight junction protein occludin in a hydroxylase-independent manner. We further find that PHD3-inhibited colon cancer cell metastasis is rescued by knockdown of occludin and that occludin acts as a negative regulator of cell metastasis, implying that PHD3 suppresses metastasis through occludin. Furthermore, knockdown of occludin induces phosphorylation of p38 MAPK, and the p38 inhibitor SB203580 impedes cell migration and invasion induced by occludin knockdown, indicating that occludin functions through p38. Moreover, knockdown of occludin enhances the expression of MKK3/6, the upstream kinase of p38, while overexpression of occludin decreases its expression. Our results suggest that PHD3 inhibits the metastasis of colon cancer cells through the occludin-p38 pathway independent of its hydroxylase activity. These findings reveal a previously undiscovered mechanism underlying the regulation of cancer cell metastasis by PHD3 and highlight a noncanonical hydroxylase-independent function of PHD3 in the suppression of cancer cells.

Alternating current stimulation promotes neurite outgrowth and plasticity in neurons through activation of the PI3K/AKT signaling pathway.

As a commonly used physical intervention, electrical stimulation (ES) has been demonstrated to be effective in the treatment of central nervous system disorders. Currently, researchers are studying the effects of electrical stimulation on individual neurons and neural networks, which are dependent on factors such as stimulation intensity, duration, location, and neuronal properties. However, the exact mechanism of action of electrical stimulation remains unclear. In some cases, repeated or prolonged electrical stimulation can lead to changes in the morphology or function of the neuron. In this study, immunofluorescence staining and Sholl analysis are used to assess changes in the neurite number and axon length to determine the optimal pattern and stimulation parameters of ES for neurons. Neuronal death and plasticity are detected by TUNEL staining and microelectrode array assays, respectively. mRNA sequencing and bioinformatics analysis are applied to predict the key targets of the action of ES on neurons, and the identified targets are validated by western blot analysis and qRT-PCR. The effects of alternating current stimulation (ACS) on neurons are more significant than those of direct current stimulation (DCS), and the optimal parameters are 3 μA and 20 min. ACS stimulation significantly increases the number of neurites, the length of axons and the spontaneous electrical activity of neurons, significantly elevates the expression of growth-associated protein-43 (GAP-43) without significant changes in the expression of neurotrophic factors. Furthermore, application of PI3K/AKT-specific inhibitors significantly abolishes the beneficial effects of ES on neurons, confirming that the PI3K/AKT pathway is an important potential signaling pathway in the action of ES.

TXNIP aggravates cardiac fibrosis and dysfunction after myocardial infarction in mice by enhancing the TGFB1/Smad3 pathway and promoting NLRP3 inflammasome activation.

Myocardial infarction (MI) results in high mortality. The size of fibrotic scar tissue following MI is an independent predictor of MI outcomes. Thioredoxin-interacting protein (TXNIP) is involved in various fibrotic diseases. Its role in post-MI cardiac fibrosis, however, remains poorly understood. In the present study, we investigate the biological role of TXNIP in post-MI cardiac fibrosis and the underlying mechanism using mouse MI models of the wild-type (WT), Txnip-knockout ( Txnip-KO) type and Txnip-knock-in ( Txnip-KI) type. After MI, the animals present with significantly upregulated TXNIP levels, and their fibrotic areas are remarkably expanded with noticeably impaired cardiac function. These changes are further aggravated under Txnip-KI conditions but are ameliorated in Txnip-KO animals. MI also leads to increased protein levels of the fibrosis indices Collagen I, Collagen III, actin alpha 2 (ACTA2), and connective tissue growth factor (CTGF). The Txnip-KI group exhibits the highest levels of these proteins, while the lowest levels are observed in the Txnip-KO mice. Furthermore, Txnip-KI significantly upregulates the levels of transforming growth factor (TGF)B1, p-Smad3, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), Cleaved Caspase-1, and interleukin (IL)1B after MI, but these effects are markedly offset by Txnip-KO. In addition, after MI, the Smad7 level significantly decreases, particularly in the Txnip-KI mice. TXNIP may aggravate the progression of post-MI fibrosis and cardiac dysfunction by activating the NLRP3 inflammasome, followed by IL1B generation and then the enhancement of the TGFB1/Smad3 pathway. As such, TXNIP might serve as a novel potential therapeutic target for the treatment of post-MI cardiac fibrosis.

CTNNAL1 deficiency suppresses CFTR expression in HDM-induced asthma mouse model through ROCK1-CAL signaling pathway.

The downregulation of adhesion molecule catenin alpha-like 1 (CTNNAL1) in airway epithelial cells of asthma patients and house dust mite (HDM)-induced asthma animal models was illustrated in our previous study. It is assumed to contribute to airway inflammation and mucus hypersecretion. In this work, we further explore the underlying mechanism of CTNNAL1 in asthma. CTNNAL1-silenced female mice exhibit a decreased level of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated and ATP-gated Cl - channel that correlates with mucus hypersecretion. Our previous study demonstrated that ROCK1 expression decreases but ROCK2 expression increases in the lungs of a CTNNAL1-silenced mouse model. Inhibition of ROCK1 leads to a reduction in CFTR expression in CTNNAL1-overexpressing and CTNNAL1-silenced human bronchial epithelial (HBE) cells. It has been reported that ROCK1 is a downstream target of RhoA and that activation of RhoA increases CFTR expression after CTNNAL1 deficiency in vitro and in vivo. The above results indicate that CTNNAL1 regulates CFTR expression through the ROCK1 pathway. In addition, the expression of CFTR-associated ligand (CAL) is increased after CTNNAL1 silencing, and immunoprecipitation results confirm the interaction between ROCK1 and CAL. Inhibition of CAL does not influence ROCK1 expression but increases CFTR expression in CTNNAL1-silenced HBE cells. These data suggest that CTNNAL1 deficiency decreases CFTR expression in the HDM-induced asthma mouse model through the ROCK1-CAL signaling pathway.