Volume III: Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases

Editors

Leming Sun

Northwestern Polytechnical University

Zhen Fan

Tongji University

Zhe-Sheng Chen

St. John's University

Impact

Original Research

31 May 2023

Single-cell RNA-seq uncovers distinct pathways and genes in endothelial cells during atherosclerosis progression

Min Wu

, 3 more and

Yueheng Wu

Identification of common marker genes in endothelial cells between human AS and ApoE−/− mice model. (A) Highly variable genes in ApoE−/− mice endothelial cells. (B) Heat maps depicting the top 30 genes in the first three PCs. (C) Bubble diagrams showing the most significantly enriched 10 GO enrichment analysis results including biological process, cellular component, and molecular function. (D) Venn diagram depicting 584 common genes between human AS coronary endothelial cells and ApoE−/− mice endothelial cells.

Background: Atherosclerosis (AS) is a chronic inflammatory disease involving various cell types, cytokines, and adhesion molecules. Herein, we aimed to uncover its key molecular mechanisms by single-cell RNA-seq (scRNA-seq) analysis.

Methods: ScRNA-seq data of cells from atherosclerotic human coronary arteries were analyzed using the Seurat package. Cell types were clustered, and differentially expressed genes (DEGs) were screened. GSVA (Gene Set Variation Analysis) scores of hub pathways were compared among different cell clusters. DEGs in endothelial cells between apolipoprotein-E (ApoE)^−/− mice and specific TGFbR1/2 KO ApoE^−/− mice fed with high-fat diet were overlapped with those from human AS coronary arteries. In fluid shear stress and AS, hub genes were determined based on the protein–protein interaction (PPI) network, which were verified in ApoE^−/− mice. Finally, hub genes were validated in three pairs of AS coronary arteries and normal tissues by histopathological examination.

Results: ScRNA-seq identified nine cell clusters in human coronary arteries, namely, fibroblasts, endothelial cells, macrophages, B cells, adipocytes, HSCs, NK cells, CD8⁺ T cells, and monocytes. Among them, endothelial cells had the lowest fluid shear stress and AS and TGF-beta signaling pathway scores. Compared to ApoE^−/− mice fed with normal diet, fluid shear stress and AS and TGF-beta scores were both significantly lower in endothelial cells from TGFbR1/2 KO ApoE^−/− mice fed with normal or high-fat diet. Furthermore, the two hub pathways had a positive correlation. Three hub genes (ICAM1, KLF2, and VCAM1) were identified, and their expression was distinctly downregulated in endothelial cells from TGFbR1/2 KO ApoE^−/− mice fed with normal or high-fat diet than in those from ApoE^−/− mice fed with a normal diet, which were confirmed in human AS coronary artery.

Conclusion: Our findings clarified the pivotal impacts of pathways (fluid shear stress and AS and TGF-beta) and genes (ICAM1, KLF2, and VCAM1) in endothelial cells on AS progression.

5,455 views

0 citations

Original Research

15 May 2023

Comprehensive analysis to construct a novel immune-related prognostic panel in aging-related gastric cancer based on the lncRNA‒miRNA-mRNA ceRNA network

Cuncan Deng

, 9 more and

Changhua Zhang

2,497 views

0 citations

Original Research

24 April 2023

LTF induces senescence and degeneration in the meniscus via the NF-κB signaling pathway: A study based on integrated bioinformatics analysis and experimental validation

Jun Zhang

, 7 more and

Biao Chen

Background: The functional integrity of the meniscus continually decreases with age, leading to meniscal degeneration and gradually developing into osteoarthritis (OA). In this study, we identified diagnostic markers and potential mechanisms of action in aging-related meniscal degeneration through bioinformatics and experimental verification.

Methods: Based on the GSE98918 dataset, common differentially expressed genes (co-DEGs) were screened using differential expression analysis and the WGCNA algorithm, and enrichment analyses based on Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were further performed. Next, the co-DEGs were imported into the STRING database and Cytoscape to construct a protein‒protein interaction (PPI) network and further validated by three algorithms in cytoHubba, receiver operating characteristic (ROC) curve analysis and the external GSE45233 dataset. Moreover, the diagnostic marker lactotransferrin (LTF) was verified in rat models of senescence and replicative cellular senescence via RT‒qPCR, WB, immunohistochemistry and immunofluorescence, and then the potential molecular mechanism was explored by loss of function and overexpression of LTF.

Results: According to the analysis of the GSE98918 dataset, we identified 52 co-DEGs (42 upregulated genes and 10 downregulated genes) in the OA meniscus. LTF, screened out by Cytoscape, ROC curve analysis in the GSE98918 dataset and another external GSE45233 dataset, might have good predictive power in meniscal degeneration. Our experimental results showed that LTF expression was statistically increased in the meniscal tissue of aged rats (24 months) and senescent passage 5th (P5) meniscal cells. In P5 meniscal cells, LTF knockdown inhibited the NF-κB signaling pathway and alleviated senescence. LTF overexpression in passage 0 (P0) meniscal cells increased the expression of senescence-associated secretory phenotype (SASP) and induced senescence by activating the NF-κB signaling pathway. However, the senescence phenomenon caused by LTF overexpression could be reversed by the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC).

Conclusion: For the first time, we found that increased expression of LTF was observed in the aging meniscus and could induce meniscal senescence and degeneration by activating the NF-κB signaling pathway. These results revealed that LTF could be a potential diagnostic marker and therapeutic target for age-related meniscal degeneration.

4,460 views

7 citations

Review

02 March 2023

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

Tong-Mei Yang

, 5 more and

Shou-Dong Guo

Macrophages are involved in the whole process of atherosclerosis, which is characterized by accumulation of lipid and inflammation. Presently, clinically used lipid-lowering drugs cannot completely retard the progress of atherosclerosis. Liver X receptor (LXR) plays a key role in regulation of lipid metabolism and inflammation. Accumulating evidence have demonstrated that synthetic LXR agonists can significantly retard the development of atherosclerosis. However, these agonists induce sever hypertriglyceridemia and liver steatosis. These side effects have greatly limited their potential application for therapy of atherosclerosis. The rapid development of drug delivery system makes it possible to delivery interested drugs to special organs or cells using nanocarriers. Macrophages express various receptors which can recognize and ingest specially modified nanocarriers loaded with LXR agonists. In the past decades, a great progress has been made in this field. These macrophage-targeted nanocarriers loaded with LXR agonists are found to decrease atherosclerosis by reducing cholesterol accumulation and inflammatory reactions. Of important, these nanocarriers can alleviate side effects of LXR agonists. In this article, we briefly review the roles of macrophages in atherosclerosis, mechanisms of action of LXR agonists, and focus on the advances of macrophage-targeted nanocarriers loaded with LXR agonists. This work may promote the potential clinical application of these nanocarriers.

3,498 views

9 citations

Original Research

20 March 2023

Symptoms of depression, perceived social support, and medical coping modes among middle-aged and elderly patients with type 2 diabetes

Chuanyan Zhang

, 3 more and

Kaijian Hou

2,579 views

2 citations

Open for submission

Frontiers in Molecular Biosciences

Cellular and Biochemical Applications & Advances in Rare Diseases: Unravelling the Mysteries of Rare Diseases Through Cutting-Edge Technologies and Innovative Research.

Edited by Mohamed Taha Moutaoufik, Hector Rodriguez Cetina Biefer, Abdallah Elkhal

Deadline

02 December 2023

Submit a paper

Frontiers in Pharmacology

Coronavirus Disease (COVID-19): Molecular Mechanisms, Translational Approaches and Therapeutics

Edited by José A G Agúndez, William C Cho, Francesco Luigi Gervasio, Shozeb Haider, Xian-Tao Zeng, Paola Patrignani, Roberto Paganelli, Dieter Steinhilber, Serena Sanna, Bengt Fadeel, Gaetano Santulli, Zbigniew R. Struzik, Yoram Vodovotz, Yu Ru Kou, Fatih M. Uckun, Paolo Montuschi, Hasan Uludag, Chen Liang, Pier Paolo Piccaluga, Gianni Ciofani, Mohib Uddin