Objective: The purpose of this study is to investigate the expression and regulation of type-2 tissue factor pathway inhibitor (TFPI-2) in endothelial cells, as well as the regulation of human endothelial cell (EC) function by TFPI-2.
Methods And Results: Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that vascular endothelial growth factor (VEGF) induced both time- and dose-dependent increase in TFPI-2 mRNA and protein expression in endothelial cells. TFPI-2 mRNA expression was also significantly upregulated by IL-1beta, and modestly increased by both tumor necrosis factor (TNF)-alpha and fibroblast growth factor (FGF)-2, but not placental growth factor (PlGF). VEGF upregulation of TFPI-2 was dramatically reduced by inhibition of the MEK pathway. Administration of TFPI-2 protein suppressed both VEGF and FGF-2 stimulation of EC proliferation in a dose-dependent manner. A recombinant preparation of the first Kunitz-type domain of TFPI-2 (KD1) did not suppress growth factor stimulation of EC proliferation, suggesting a mechanism distinct from the proteinase inhibitory activity of TFPI-2. Exogenously added TFPI-2 protein suppressed VEGF-induced EC migration in 2 different assays. Recombinant wt-KD1 or the R24K mutant of KD1, but not the R24Q mutant, dramatically suppressed VEGF-induced EC migration. TFPI-2 protein, but not recombinant KD1, blocked VEGF-induced activation of both Akt and ERK1/2 in ECs. At higher doses, TFPI-2 protein blocked VEGFR2 activation.
Conclusions: Our data suggest that VEGF-upregulation of TFPI-2 expression in endothelial cells may represent a mechanism for negative feedback regulation and modulation of its pro-angiogenic action on endothelial cells. TFPI-2, or derivatives of TFPI-2, may be novel therapeutics for treatment of angiogenic disease processes.
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http://dx.doi.org/10.1161/01.ATV.0000248731.55781.87 | DOI Listing |
Int J Surg
January 2025
Department of Anesthesiology, Jiangxi Cancer Hospital & Institute, Jiangxi Clinical Research Center for Cancer, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Key Laboratory of Oncology, Nanchang, Jiangxi Province, China.
Nerve growth factor (NGF) is critical in regulating the homeostasis of microglial cells. It activates various signaling pathways that mediate the phosphorylation of cAMP response element-binding protein (CREB) at key regulatory sites. The decrease in phosphorylated CREB (p-CREB) expression is linked to neuroinflammatory responses.
View Article and Find Full Text PDFInt J Surg
January 2025
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Although several chemotherapy regimens have been developed over the past decades, few targeted therapies have shown a significant improvement in overall survival, partly due to the identification of PDAC as a single disease.
Methods: Combining metabolomic analysis and immunohistochemistry staining with Oil Red O staining, analysis for the oxygen consumption rate and extracellular acidification rate, we stratified pancreatic cancer cells into two subtypes.
Biomol Biomed
January 2025
Necmettin Erbakan University, Meram Faculty of Medicine, Department of Medical Oncology, Konya, Turkey.
The cysteine-rich epidermal growth factor ligand domain 2 protein (CRELD2) is associated with pathways that regulate epithelial-to-mesenchymal transition, a critical process driving cancer metastasis. This study aimed to determine the prognostic value of CRELD2 status on survival outcomes in triple-negative breast cancer (TNBC). Seventy patients were included in the study.
View Article and Find Full Text PDFAnticancer Drugs
January 2025
Department of General Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center.
In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment.
View Article and Find Full Text PDFJAMA Neurol
January 2025
Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore.
Importance: Biomarkers would greatly assist decision-making in the diagnosis, prevention, and treatment of chronic pain.
Objective: To undertake analytical validation of a sensorimotor cortical biomarker signature for pain consisting of 2 measures: sensorimotor peak alpha frequency (PAF) and corticomotor excitability (CME).
Design, Setting, And Participants: This cohort study at a single center (Neuroscience Research Australia) recruited participants from November 2020 to October 2022 through notices placed online and at universities across Australia.
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