Polymeric Amines Induce Nitric Oxide Release from S-Nitrosothiols

Catalytic generation of nitric oxide (NO) from NO donors by nanomaterials has enabled prolonged NO delivery for various biomedical applications, but this approach requires laborious synthesis routes. In this study, a new class of materials, that is, polymeric amines including polyethyleneimine (PEI), poly-L-lysine, and poly(allylamine hydrochloride), is discovered to induce NO generation from S-nitrosothiols (RSNOs) at physiological conditions. Controlled NO generation can be readily achieved by tuning the concentration of the NO donors (RSNOs) and polymers, and the type and molecular weight of the polymers. Importantly, the mechanism of NO generation by these polymers is deciphered to be attributed to the nucleophilic reaction between primary amines on polymers and the SNO groups of RSNOs. The NO-releasing feature of the polymers can be integrated into a suite of materials, for example, simply by embedding PEI into poly(vinyl alcohol) (PVA) hydrogels. The functionality of the PVA/PEI hydrogels is demonstrated for Pseudomonas aeruginosa biofilm prevention with a ≈ 4 log reduction within 6 h. As NO has potential therapeutic implications in various diseases, the identification of polymeric amines to induce NO release will open new opportunities in NO-generating biomaterials for antibacterial, antiviral, anticancer, antithrombotic, and wound healing applications.     

Modeling of S‐Nitrosothiol–Thiol Reactions of Biological Significance: HNO Production by S‐Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates

Nitroxyl (HNO), a reduced form of the important gasotransmitter nitric oxide, exhibits its own unique biological activity. A possible biological pathway of HNO formation is the S‐thiolation reaction between thiols and S‐nitrosothiols (RSNOs). Our density functional theory (DFT) calculations suggested that S‐thiolation proceeds through a proton transfer from the thiol to the RSNO nitrogen atom, which increases electrophilicity of the RSNO sulfur, followed by nucleophilic attack by thiol, yielding a charge‐separated zwitterionic intermediate structure RSS⁺(R)N(H)O^? ( Zi ), which decomposes to yield HNO and disulfide RSSR. In the gas phase, the proton transfer and the S?S bond formation are asynchronous, resulting in a high activation barrier (>40 kcal mol^?1), making the reaction infeasible. However, the barrier can decrease below the S?N bond dissociation energy in RSNOs (≈30 kcal mol^?1) upon transition into an aqueous environment that stabilizes Zi and provides a proton shuttle to synchronize the proton transfer and the S?S bond formation. These mechanistic features suggest that S‐thiolation can easily lend itself to enzymatic catalysis and thus can be a possible route of endogenous HNO production.     

Transient Vasodilation in Mouse 4T1 Tumors after Intragastric and Intravenous Administration of Gold Nanoparticles

Gold nanoparticles (AuNPs) are foreseen as a promising tool in nanomedicine, both as drug carriers and radiosensitizers. They have been also proposed as a potential anticancer drug due to the anti-angiogenic effect in tumor tissue. In this work we investigated the effect of citrate-coated AuNPs of nominal diameter 20 nm on the growth and metastatic potential of 4T1 cells originated from a mouse mammary gland tumor inoculated into the mammary fat pad of Balb/ccmdb mice. To evaluate whether AuNPs can prevent the tumor growth, one group of inoculated mice was intragastrically (i.g.) administered with 1 mg/kg of AuNPs daily from day 1 to day 14 after cancer cell implantation. To evaluate whether AuNPs can attenuate the tumor growth, the second group was intravenously (i.v.) administered with 1 or 5 mg/kg of AuNPs, twice on day 5 and day 14 after inoculation. We did not observe any anticancer activity of i.v. nor i.g. administered AuNPs, as they did not affect neither the primary tumor growth rate nor the number of lung metastases. Unexpectedly, both AuNP treatment regimens caused a marked vasodilating effect in the tumor tissue. As no change of potential angiogenic genes (Fgf2, Vegfa) nor inducible nitric oxygenase (Nos2) was observed, we proposed that the vasodilation was caused by AuNP-dependent decomposition of nitrosothiols and direct release of nitric oxide in the tumor tissue.     

Blood Plasma’s Protective Ability against the Degradation of S-Nitrosoglutathione under the Influence of Air-Pollution-Derived Metal Ions in Patients with Exacerbation of Heart Failure and Coronary Artery Disease

One of the consequences of long-term exposure to air pollutants is increased mortality and deterioration of life parameters, especially among people diagnosed with cardiovascular diseases (CVD) or impaired respiratory system. Aqueous soluble inorganic components of airborne particulate matter containing redox-active transition metal ions affect the stability of S-nitrosothiols and disrupt the balance in the homeostasis of nitric oxide. Blood plasma’s protective ability against the decomposition of S-nitrosoglutathione (GSNO) under the influence of aqueous PM extract among patients with exacerbation of heart failure and coronary artery disease was studied and compared with a group of healthy volunteers. In the environment of CVD patients’ plasma, NO release from GSNO was facilitated compared to the plasma of healthy controls, and the addition of ascorbic acid boosted this process. Model studies with albumin revealed that the amount of free thiol groups is one of the crucial factors in GSNO decomposition. The correlation between the concentration of NO released and -SH level in blood plasma supports this conclusion. Complementary studies on gamma-glutamyltranspeptidase activity and ICP-MS multielement analysis of CVD patients’ plasma samples in comparison to a healthy control group provide broader insights into the mechanism of cardiovascular risk development induced by air pollution.