Integration of single‐cell RNA sequencing of endothelial cells and proteomics to unravel the role of ICAM1–PTGS2 communication in apical periodontitis: A laboratory investigation

Article

Author: Huang, Yihua ; Lv, Xiaomin ; Gong, Qimei ; Quan, Jingjing ; Tong, Zhongchun ; Luo, Cuiting ; Wu, Jie

AbstractAimEndothelial cells (EDs) play a key role in angiogenesis and are associated with granulomatous lesions in patients with chronic apical periodontitis (CAP). This study aimed to investigate the diversity of EDs using single‐cell ribonucleic acid sequencing (scRNA‐seq) and to evaluate the regulation of intercellular adhesion molecule 1 (ICAM1) on the ferroptosis‐related protein, prostaglandin‐endoperoxide synthase 2 (PTGS2), in CAP.MethodologyEDs from the uploaded scRNA‐seq data of five CAP samples (GSE181688 and GSE197680) were categorized using distinct marker genes. The interactions between vein EDs (veinEndo) and other cell types were analysed using CellPhoneDB. Differentially expressed proteins in the proteomics of human umbilical vein EDs (HUVECs) and THP‐1‐derived macrophages infected with Porphyromonas gingivalis were compared with the differentially expressed genes (DEGs) of VeinEndo in scRNA‐seq of CAP versus healthy control periodontal tissues. The protein–protein interaction of ICAM1–PTGS2 in macrophages and HUVECs was validated by adding recombinant ICAM1, ICAM1 inhibitor and PTGS2 inhibitor using real‐time polymerase chain reaction (PCR), western blotting, and immunofluorescence staining.ResultsEDs in patients with CAP were divided into eight subclusters: five vein ED, capillaries, arterials and EC (PLA). There were 29 mutually upregulated DEGs and two mutually downregulated DEGs in vein cells in the scRNA‐seq data, as well as differentially expressed proteins in the proteomics of HUVECs. Real‐time PCR and immunofluorescence staining showed that ICAM1 and PTGS2 were highly expressed in CAP, infected HUVECs, and macrophages. Recombinant protein ICAM1 may improve PTGS2 expression, reactive oxygen species (ROS), and Fe2+ levels and decrease glutathione peroxidase 4 (GPX4) and SLC7A11 protein levels. ICAM1 inhibitor may inverse the above changes.ConclusionsscRNA‐seq revealed the diversity of EDs in CAP and identified the possible regulation of ICAM1 by the ferroptosis‐related protein, PTGS2, in infected HUVECs and macrophages, thus providing a basis for therapeutic approaches that target the inflammatory microenvironment of CAP.

Cell Biochemistry and Biophysics

Molecular Regulator Driving Endometriosis Towards Endometrial Cancer: A Multi-Scale Computational Investigation to Repurpose Anti-Cancer drugs

Article

Author: Ahmed, Shiek S S J ; Mahema, S ; Al-Mazroua, Haneen A ; Roshni, Jency ; Ahmad, Sheikh F ; Raman, Janaki

Endometriosis is a gynecological disorder among reproductive-aged women. Recent epidemiological investigations suggest endometriosis increases the risk of endometrial cancer. However, the molecular entity leading to endometriosis-to-endometrial cancer is largely unknown. This study aimed to combine a variety of computational approaches to identify the key therapeutic target promoting endometriosis-to-endometrial cancer and screen potential inhibitors against target to prevent cancer development. Our systematic investigations, includes transcriptomic profiling, protein network, pharmacophore modeling, docking, binding free energy calculation, dynamics simulation, and quantum mechanics. The gene expression analysis on endometriosis and endometrial cancer was performed and showed 108 shared upregulated genes in both conditions. Further construction of interaction network with 108 genes showed intercellular adhesion molecule 1 (ICAM1) to be a crucial molecule with a high degree of connectivity that influences vital mechanisms related to cancer pathways. We then generated ligand-based pharmacophore models using established ICAM1 inhibitors. Among the models, the ADRRR_8 pharmacophore exhibited a robust area under curve (AUC = 0.83), was employed to screen 1739 anti-cancer drugs. On screening, 421 anti-cancer drugs displayed ICAM1-inhibiting pharmacophore features. Further, the docking of 421 drugs with ICAM1 showed lanreotide (-7.80 kcal/mol) with better affinity than the reference ICAM1 inhibitor (-3.59 kcal/mol). Further validation though binding free energy and dynamics simulation of the lanreotide-ICAM1 complex showed a high binding affinity of -55.90 kcal/mol and contributed stable confirmation. According to quantum chemical calculations, lanreotide's electronic properties favour ICAM1 binding with highest occupied molecular orbital was -6.91 eV and lowest unoccupied molecular orbital was -3.93 eV. Our study supports using lanreotide to treat endometriosis, which could delay or prevent endometrial cancer. These predictions need to be confirmed and examined to determine the use of lanreotide in endometriosis treatment.

100 Deals associated with ICAM1 targeting ADC(TianJin University)

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Indication	Highest Phase	Country/Location	Organization	Date
Uterine Cervical Cancer	Preclinical	CN	Zhejiang Cancer Hospital	08 Apr 2024
Uterine Cervical Cancer	Preclinical	CN	Tianjin University	08 Apr 2024
Thyroid Cancer	Preclinical	CN	Tianjin University	13 Aug 2023
Thyroid Cancer	Preclinical	CN	Zhejiang Cancer Hospital	13 Aug 2023

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