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Adhesion of circulating tumor cells (CTCs) to vascular endothelial bed becomes a crucial starting point in metastatic cascade. We hypothesized that nitric oxide (NO) may prevent cancer metastasis from happening by its direct vasodilation and inhibition of cell adhesion molecules (CAMs). Here we show that S-nitrosocaptopril (CAP-NO, a typical NO donor) produced direct vasorelaxation that can be antagonized by typical NO scavenger hemoglobin and guanylate cyclase inhibitor. Cytokines significantly stimulated production of typical CAMs by the highly-purified human umbilical vein endothelial cells (HUVECs). CAP-NO inhibited expression of the stimulated CAMs (particularly VCAM-1) and the resultant hetero-adhesion of human colorectal cancer cells HT-29 to the HUVECs in a concentration-dependent manner. The same concentration of CAP-NO, however, did not significantly affect cell viability, cell cycle and mitochondrial membrane potential of HT-29, thus excluding the possibility that inhibition of the hetero-adhesion was caused by cytotoxicity by CAP-NO on HT-29. Hemoglobin reversed the inhibition of CAP-NO on both the hetero-adhesion between HT-29 and HUVECs and VCAM-1 expression. These data demonstrate that CAP-NO, by directly releasing NO, produces vasorelaxation and interferes with hetero-adhesion of cancer cells to vascular endothelium via down-regulating expression of CAMs. The study highlights the importance of NO in cancer metastatic prevention.

Orthopaedic implants require surfaces that resist bacterial colonisation while supporting host cell compatibility. In this study, we fabricated highly interconnected porous titanium (Ti) foams using a cost‑effective sintering–dissolution process (SDP) and functionalised them with 11‑aminoundecyltriethoxysilane (AUTES) and covalently tethered N -diazeniumdiolate nitric oxide (NO) donors. Structural characterisation by Scanning electron microscopy, X‑ray micro‑CT, and Brunauer–Emmett–Teller analyses confirmed a hierarchical porous architecture with ~ 73% total porosity and extensive internal surface area, enabling efficient chemical functionalisation. Chemiluminescence analysis demonstrated formulation‑dependent NO payloads and sustained release for over 15 h in bacterial culture medium. The NO‑releasing foams significantly reduced biofilm-associated Escherichia coli and Staphylococcus aureus compared with untreated controls, with the 20% AUTES/NO formulation showing the most persistent antibiofilm activity at 24 h ( p  < 0.05). Limited effects were observed against planktonic bacteria. Human mesenchymal stem cells (hMSCs) adhered to and remained viable on both unmodified and functionalised foams over 7 days, indicating cytocompatibility of the surface modification following NO release. These findings demonstrate that SDP-derived porous Ti foams can be functionalised for localised NO delivery and effective antibiofilm activity while maintaining initial hMSC compatibility, offering a scalable platform for multifunctional Ti-based implant surfaces.

Herein, we report the synthesis of a new hybrid compound based on a 2′-deoxyuridine nucleoside conjugated with a NO photo-donor moiety (dU-t-NO) via CuAAC click chemistry. Hybrid dU-t-NO, as well as two previously reported 2′-deoxyadenosine based hybrids (dAdo-S-NO and dAdo-t-NO), were evaluated for their cytotoxic and cytostatic activities in selected cancer cell lines. dAdo-S-NO and dAdo-t-NO hybrids displayed higher activity with respect to dU-t-NO. All hybrids showed effective release of NO in the micromolar range. The photochemical behavior of the newly reported hybrid, dU-t-NO, was studied in the RKO colon carcinoma cell line, whereas the dAdo-t-NO hybrid was tested in both colon carcinoma RKO and hepatocarcinoma Hep 3B2.1-7 cell lines to evaluate the potential effect of NO released upon irradiation on cell viability. A customized irradiation apparatus for in vitro experiments was also designed.

The acidic byproducts of bacteria in plaque around orthodontic brackets contribute to white spot lesion (WSL) formation. Nitric oxide (NO) has antibacterial properties, hindering biofilm formation and inhibiting the growth of oral microbes. Materials that mimic NO release could prevent oral bacteria-related pathologies. This study aims to integrate S-nitroso-acetylpenicillamine (SNAP), a promising NO donor, into orthodontic elastomeric ligatures, apply an additional polymer coating, and evaluate the NO-release kinetics and antimicrobial activity against Streptococus mutans. SNAP was added to clear elastomeric chains (8 loops, 23 mm long) at three concentrations (50, 75, 100 mg/mL, and a control). Chains were then coated, via electrospinning, with additional polymer (Elastollan®) to aid in extending the NO release. NO flux was measured daily for 30 days. Samples with 75 mg/mL SNAP + Elastollan® were tested against S. mutans for inhibition of biofilm formation on and around the chain. SNAP was successfully integrated into ligatures at each concentration. Only the 75 mg/mL SNAP chains maintained their elasticity. After polymer coating, samples exhibited a significant burst of NO on the first day, exceeding the machine’s reading capacity, which gradually decreased over 29 days. Ligatures also inhibited S. mutans growth and biofilm formation. Future research will assess their mechanical properties and cytotoxicity. This study presents a novel strategy to address white spot lesion (WSL) formation and bacterial-related pathologies by utilizing nitric oxide-releasing materials. Manufactured chains with antimicrobial properties provide a promising solution for orthodontic challenges, showing significant potential for academic-industrial collaboration and commercial viability.

NOSs are homodimeric multidomain enzymes responsible for producing NO. In mammals, NO acts as an intercellular messenger in a variety of signaling reactions, as well as a cytotoxin in the innate immune response. Mammals possess three NOS isoforms— inducible, endothelial, and neuronal NOS—that are composed of an N-terminal oxidase domain and a C-terminal reductase domain. Calmodulin (CaM) activates NO synthesis by binding to the helical region connecting these two domains. Although crystal structures of isolated domains have been reported, no structure is available for full-length NOS. We used high-throughput single-particle EM to obtain the structures and higher-order domain organization of all three NOS holoenzymes. The structures of inducible, endothelial, and neuronal NOS with and without CaM bound are similar, consisting of a dimerized oxidase domain flanked by two separated reductase domains. NOS isoforms adopt many conformations enabled by three flexible linkers. These conformations represent snapshots of the continuous electron transfer pathway from the reductase domain to the oxidase domain, which reveal that only a single reductase domain participates in electron transfer at a time, and that CaM activates NOS by constraining rotational motions and by directly binding to the oxidase domain. Direct visualization of these large conformational changes induced during electron transfer provides significant insight into the molecular underpinnings governing NO formation.

Ocular infection due to microbial contamination is one of the main risks associated with the wearing of contact lens, which demands novel straightforward strategies to find reliable solutions. This contribution reports the preparation, characterization and biological evaluation of soft contact lenses (CL) releasing nitric oxide (NO), as an unconventional antibacterial agent, under daylight exposure. A tailored NO photodonor (NOPD) was embedded into commercial CL leading to doped CL with an excellent optical transparency (transmittance = 100%) at λ ≥ 450 nm. The NOPD results homogeneously distributed in the CL matrix where it fully preserves the photobehavior exhibited in solution. In particular, NO release from the CL and its diffusion in the supernatant physiological solution is observed upon visible light illumination. The presence of a blue fluorescent reporting functionality into the molecular skeleton of the NOPD, which activates concomitantly to the NO photorelease, allows the easy monitoring of the NO delivery in real-time and confirms that the doped CL work under daylight exposure. The NO photoreleasing CL are well-tolerated in both dark and light conditions by corneal cells while being able to induce good growth inhibition of Staphylococcus aureus under visible light irradiation. These results may pave the way to further engineering of the CL with NOPD as innovative ocular devices activatable by sunlight.

Various nitric oxide modulators (NO donors--SNP, GSNO, DEA NONOate and scavengers--PTIO, cPTIO) were tested to highlight the role of NO under Cd excess in various ontogenetic stages of chamomile (Matricaria chamomilla). Surprisingly, compared to Cd alone, SNP and PTIO elevated Cd uptake (confirmed also by PhenGreen staining) but depleted glutathione (partially ascorbic acid) and phytochelatins PC2 and PC3 in both older plants (cultured hydroponically) and seedlings (cultured in deionised water). Despite these anomalous impacts, fluorescence staining of NO and ROS confirmed predictable assumptions and revealed reciprocal changes (decrease in NO but increase in ROS after PTIO addition and the opposite after SNP application). Subsequent tests using alternative modulators and seedlings confirmed changes to NO and ROS after application of GSNO and DEA NONOate as mentioned above for SNP while cPTIO altered only NO level (depletion). On the contrary to SNP and PTIO, GSNO, DEA NONOate and cPTIO did not elevate Cd content and phytochelatins (PC2, PC3) were rather elevated. These data provide evidence that various NO modulators are useful in terms of NO and ROS manipulation but interactions with intact plants affect metal uptake and must therefore be used with caution. In this view, cPTIO and DEA NONOate revealed the less pronounced side impacts and are recommended as suitable NO scavenger/donor in plant physiological studies under Cd excess.

Photodynamic therapy (PDT) utilizes photosensitizers to generate reactive oxygen species (ROS) to kill tumors. However, the tumor's hypoxia and the limitations of a single ROS mechanism severely restrict its efficacy. This study aims to develop a synergistic nano-catalytic system (HMO) based on hollow manganese dioxide (HMnO ) loaded with a novel nitric oxide (NO) donor (Methylene Blue - NO, MB-NO), which overcomes these obstacles through multiple synergistic effects. Preliminary experiments confirmed the synthesis of HMO. Systematic studies were conducted on the chemodynamic therapy (CDT)/PDT/NO properties of HMO as well as its anti-tumor activity in vivo and in vitro. Finally, the in vivo safety of HMO was evaluated. Preparation by the HMO is 189 nm nano particle size, Zeta potential for -37 ± 1.4 mV, exhibit excellent stability. In vitro experiments showed that the cellular uptake of HMO was time-dependent. In terms of cytotoxicity, the cell survival rate of the HMO group was 65.9%, significantly lower than that of the free HMnO (89.1%) and MB-NO (85.1%); after 5 min of 660 nm laser irradiation, the cell survival rate of the HMO group further dropped to 48.5%. In the animal experiments of tumor xenograft models, the tumor inhibition rate of the HMO combined with 660 nm laser irradiation for 5 min group was as high as 81.3%, and it did not cause acute inflammation in the main organs, demonstrating good biological safety. In summary, the HMO nanoparticles exhibit excellent anti-tumor effects. This strategy combines CDT/PDT/gas therapy, enabling the synergistic cascade of NO/ROS/reactive nitrogen oxide species (RNOS) to promote tumor cell apoptosis and inhibit tumor growth, thereby achieving a cascading amplification of therapeutic effects and providing a treatment solution to overcome the inherent limitations of traditional photodynamic therapy.

Hydrogen sulfide (H2S) and nitric oxide (NO) are major gasotransmitters produced in endothelial cells (ECs), contributing to the regulation of vascular contractility and structural integrity. Their interaction at different levels would have a profound impact on angiogenesis. Here, we showed that H2S and NO stimulated the formation of new microvessels. Incubation of human umbilical vein endothelial cells (HUVECs‐926) with NaHS (a H2S donor) stimulated the phosphorylation of endothelial NO synthase (eNOS) and enhanced NO production. H2S had little effect on eNOS protein expression in ECs. L‐cysteine, a precursor of H2S, stimulated NO production whereas blockage of the activity of H2S‐generating enzyme, cystathionine gamma‐lyase (CSE), inhibited this action. CSE knockdown inhibited, but CSE overexpression increased, NO production as well as EC proliferation. LY294002 (Akt/PI3‐K inhibitor) or SB203580 (p38 MAPK inhibitor) abolished the effects of H2S on eNOS phosphorylation, NO production, cell proliferation and tube formation. Blockade of NO production by eNOS‐specific siRNA or nitro‐L‐arginine methyl ester (L‐NAME) reversed, but eNOS overexpression potentiated, the proliferative effect of H2S on ECs. Our results suggest that H2S stimulates the phosphorylation of eNOS through a p38 MAPK and Akt‐dependent pathway, thus increasing NO production in ECs and vascular tissues and contributing to H2S‐induced angiogenesis.

The protective role of NO has been widely verified in cerebrovascular diseases. However, the beneficial effects of NO depend on its concentration and reactive oxygen species (ROS) level, which makes current NO donors face great difficulties in treating cerebral ischemia-reperfusion injury (CIRI). Here, a tailored MoS 2 -based NO donor (MSNO) was constructed with defect-rich MoS 2 , in which the abundant S edge sites in the defects form -SNO, and the Mo sites can also bind NO to form Mo-NO. Combined with MSNO’s own strong ability to eliminate ROS, MSNO could provide pure NO at suitable concentrations like eNOS and avoid the generation of highly toxic ONOO - . After intravenous injection, MSNO with suitable nano-size could penetrate the blood-brain barrier of ischemia-reperfusion injured brain tissue, and effectively treat CIRI through multiple effects: inhibiting calcium overload, alleviating mitochondrial damage and endoplasmic reticulum stress, and inhibiting the inflammatory storm. Nitric oxide in known to have a protective effect in cerebrovascular disease. Here, the authors report on MoS 2 an eNOS mimetic which releases NO while avoiding toxic ONOO - production, demonstrating therapeutic effects in inhibiting several damage pathways in cerebral ischemia-reperfusion injury.