NOS3 (Nitric oxide synthase 3)

Targeting the VEGFR2/PLCγ/SHP2 axis-genetically or pharmacologically-reduces EC junctional phosphorylation to prevent VE-cadherin internalization, followed by reduced macromolecular leakage. Tumor EC expression of PLCγ or SHP2 is associated with vascular leakage in human kidney cancer, underscoring their potential as targets for vascular normalization and biomarkers for disease progression and treatment response.

P=N/A, N=40, Completed, Ataturk University

P=N/A, N=175, Completed, University Hospital, Rouen | Unknown status --> Completed | N=120 --> 175

Key apoptosis-associated genes, including ALDH3A1, CYP1A1, NOS3, MT1X, and CES1, were further validated by RT-qPCR. These findings suggest CNDCM as a potential candidate for breast cancer therapy.

In contrast, compound 24, the N-Me analogue of 16, was inactive. Molecular dynamics simulations indicated that N-methylation disrupted the favorable solvation of the tail amino group, likely contributing to its loss of activity and nNOS affinity.

Pharmacokinetic evaluation confirmed the brain penetrance of 4 and demonstrated a high oral bioavailability (77%). Moreover, the X-ray crystal structures of representative compounds bound to three NOS isoforms (hnNOS, rnNOS, and heNOS) revealed key binding interactions that contribute to both potency and selectivity.

Among the most studied SERMs are Tamoxifen and Raloxifene. The pharmacological profile of SERMs therefore reflects a delicate equilibrium between receptor-mediated vascular protection and thrombotic liability. Indeed, their raison d'être increasingly extends beyond oncology into cardiovascular endocrine pharmacology, where they serve as prototypes for designing next-generation agents with optimized receptor selectivity and safer vascular outcomes.

Quercetin ameliorates Ri-ED by mitigating oxidative stress, fibrosis and apoptosis, preserving endothelial and neurovascular integrity, and activating the Nrf2/HO-1 signalling pathway in both penile tissue and endothelial cells. These findings provide experimental evidence supporting quercetin as a potential adjunct therapeutic agent for preventing or treating Ri-ED in patients undergoing pelvic radiotherapy.

This is the first report of a GSH-responsive polymeric prodrug system that leverages intracellular GSH for both controlled release of anionic therapeutic agents and in situ synthesis of an iNOS antagonist. Through these two complementary pathways, the system enables targeted, sustained anti-angiogenic effects and promotes vascular normalization. This dual-function platform holds strong potential for the treatment of cancer-associated angiogenesis.

Compound 9 exhibited inhibition of both human (Ki = 1.7 nM) and rat nNOS (Ki = 2.3 nM), with 5654-fold selectivity over human eNOS and 250-fold selectivity over iNOS. X-ray crystallography and molecular modeling revealed a novel SAR, forming the basis for nNOS inhibition and providing a foundation for further innovative design of nNOS inhibitors for melanoma treatment.

These results suggest that BAIBA exerts various protective effects on vascular endothelial cells through the PGC-1β-NFκB and PGC-1β-AMPK-Akt-eNOS axes.