G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.

COL1A1 is a potential prognostic marker and therapeutic target in non-small cell lung cancer.

Background: Nowadays, non-small cell lung cancer (NSCLC) is a common and highly fatal malignancy in worldwide. Therefore, to identify the potential prognostic markers and therapeutic targets is urgent for patients. Objective: This study aims to find hub targets associated with NSCLC using multiple databases. Methods: Differentially expressed genes (DEGs) from Genome Expression Omnibus (GEO) cohorts were employed for the enrichment analyses of Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genome (KEGG) pathways. Candidate key genes, filtered from the topological parameter 'Degree' and validated using the The Cancer Genome Atlas (TCGA) cohort, were analyzed for their association with clinicopathological features and prognosis of NSCLC. Meanwhile, immunohistochemical cohort analyses and biological verification were further evaluated. Results: A total of 146 DEGs were identified following data preprocessing, and a protein-protein interaction (PPI) systematic network was constructed based on them. The top ten candidate core genes were further extracted from the above PPI network by using 'Degree' value, among which COL1A1 was shown to associate with overall survival (OS) of NSCLC as determined by using the Kaplan-Meier analysis (p=0.028), and could serve as an independent prognostic factor for OS in NSCLC patients (HR, 0.814; 95% CI, 0.665-0.996; p=0.046). We then analyzed the clinical stages, PPI, mutations, potential biological functions and immune regulations of COL1A1 in NSCLC patients using multiple bioinformatics tools, including GEPIA, GeneMANIA, cBioPortal, GESA and TISIDB. Finally, we further experimentally validated the overexpression of COL1A1 in NSCLC samples, and found that inhibition of COL1A1 expression moderately sensitized NSCLC cells to cisplatin. Conclusion: Thus, our results show that COL1A1 may serve as a potential prognostic marker and therapeutic target in NSCLC.

Identification of AHSA1 as a Potential Therapeutic Target for Breast Cancer: Bioinformatics Analysis and In Vitro Studies

Background: Shenling Baizhu Powder (SBP), a famous Traditional Chinese Medicine (TCM) formulation, has been widely used in the adjuvant treatment of cancers, including breast cancer. This study aims to identify potential new targets for breast cancer treatment based on the network pharmacology of SBP. Methods: By analyzing the relationship between herbs and target proteins, potential targets of multiple herbs in SBP were identified by network pharmacology analysis. Besides, by comparing the data of breast cancer tissue with normal tissue, upregulated genes in two breast cancer expression profiles were found. Thereafter, the expression level and prognosis of activator of heat shock protein 90 (HSP90) ATPase activity 1 (AHSA1) were further analyzed in breast cancer by bioinformatics analysis, and the network module of AHSA1 binding protein was constructed. Furthermore, the effect of knocking down AHSA1 on the proliferation, migration, and invasion of breast cancer cells was verified by MTT, clone formation assay, and transwell assay. Results: Vascular endothelial growth factor A (VEGFA), intercellular adhesion molecule 1 (ICAM1), chemokine (C-X-C motif) ligand 8 (CXCL8), AHSA1, and serpin family E member 1 (SERPINE1) were associated with multiple herbs in SBP. AHSA1 was remarkably upregulated in breast cancer tissues and positively correlated with poor overall survival and disease metastasis-free survival. Furthermore, knockdown of AHSA1 significantly inhibited the migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells but had no obvious effect on proliferation. In addition, among the proteins that bind to AHSAl, the network composed of proteasome, chaperonin, and heat shock proteins is closely connected, and these proteins are associated with poor prognosis in a variety of cancers. Conclusion: AHSA1 is positively correlated with breast cancer progression and might act as a novel therapeutic target for breast cancer.

Comprehensive bioinformatic analysis of the expression and prognostic significance of TSC22D domain family genes in acute myeloid leukemia

Background: TSC22D domain family genes, including Tsc22d1-4, have been extensively reported to be involved in tumors. However, their expression profiles and prognostic significance in acute myeloid leukemia (AML) remain unknown. Methods: The present study investigated the expression profiles and prognostic significance of TSC22D domain family genes in AML through the use of multiple online databases, including the CCLE, EMBL-EBI, HPA, Oncomine,GEPIA2, UALCAN, BloodSpot, and GSCALite databases. The cBioPortal and GSCALite databases were used to explore the genetic alteration and copy number variation (CNV) of the Tsc22d3 gene. The TRRUST (Version 2) database was used to explore the gene ontology biological process, disease ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with the Tsc22d3 gene. The AnimalTFDB3.0, STRING, and Harmonizome databases were used to investigate the protein–protein interaction (PPI) network of the Tsc22d3 gene. The Harmonizome database was used for Tsc22d3 gene regulatory kinase analysis. The TargetScanHuman 7.2, MiRDB, and ENCORI databases were used to execute the analysis of the Tsc22d3 gene regulatory miRNAs. Then, the GSCALite and GEPIA2021 databases were used to investigate the correlation between Tsc22d3 expression and immune infiltration. Results: The expression of the Tsc22d3 gene was upregulated markedly in AML cells relative to normal hematopoietic stem cells. The expression of the Tsc22d3 gene was increased in AML tumor samples compared with healthy bone marrow samples. And overexpression of the Tsc22d3 gene was associated with poor OS in AML patients.This study implied that the Tsc22d3 gene is a new biomarker for predicting the prognosis of AML. Furthermore, gene ontology analysis showed that Tsc22d3 was involved in leukemia. Functional enrichment analysis showed that the Tsc22d3 gene has many biological functions, including the regulation of many genes, kinases, miRNAs, signaling pathways, and immune infiltration.Therefore, this study suggests that the Tsc22d3 gene may be a potential therapeutic target for AML. Conclusions: Tsc22d3 gene expression was upregulated in AML, and overexpression was associated with poor OS in AML patients. Therefore, the Tsc22d3 gene may serve as a novel prognostic biomarker and therapeutic target for AML.

Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis

The Wnt pathway is involved in several processes essential for bone development and homeostasis. For proper functioning, the Wnt pathway is tightly regulated by numerous extracellular elements that act by both activating and inhibiting the pathway at different moments. This review aims to describe, summarize and update the findings regarding the extracellular modulators of the Wnt pathway, including co-receptors, ligands and inhibitors, in relation to bone homeostasis, with an emphasis on the animal models generated, the diseases associated with each gene and the bone processes in which each member is involved. The precise knowledge of all these elements will help us to identify possible targets that can be used as a therapeutic target for the treatment of bone diseases such as osteoporosis.