Nitric Oxide Services (United States)

Platinum-based chemotherapeutics remain the standard of care for many solid tumors; however, they have dose-limiting toxicities. Silver(I) N-heterocyclic carbene complexes represent a novel class of metallodrugs with potential anticancer activity and improved tolerability. This study evaluated SCC5, a silver(I) acetate complex derived from 1,3-dimethyl-4,5-dichloroimidazole-2-ylidene, across a panel of human cancer cell lines and in vivo toxicity models. Mechanistic analysis of apoptosis was also performed using caspase-8 immunoblotting. Eight human cancer cell lines (melanoma, colon, renal, bladder, ovarian, and prostate) were treated with SCC5 and three FDA-approved platinum drugs (cisplatin, carboplatin, oxaliplatin). Antiproliferative activity was measured using the sulforhodamine B assay. In vivo toxicity was assessed in CD-1 mice receiving escalating intraperitoneal doses (10-50 mg/kg), with survival monitored over 21 days. Caspase-8 was analyzed by western blotting in SCC5-treated HT-29 cells. SCC5 exhibited half-maximal inhibitory doses ranging from 10 to 30 μM, comparable to carboplatin and was slightly less potent than cisplatin and oxaliplatin. However, SCC5 demonstrated superior safety, with 100% survival at doses that were lethal to platinum compounds, supporting its more favorable therapeutic index. Western blot analysis revealed dose- and time-dependent loss of caspase-8 expression following SCC5 treatment, suggesting activation of apoptosis-related pathways. SCC5 maintains broad-spectrum antiproliferative activity with markedly improved in vivo tolerability compared to platinum drugs. These findings support continued preclinical development of SCC5 as a novel silver-based chemotherapeutic.

Intrinsic factor (IF) is a glycoprotein crucial for cobalamin (vitamin B12) absorption in the human body. This study aimed to evaluate the binding affinity of nitrosylcobalamin (NO-Cbl), a cobalamin analog, to recombinant human IF derived from plants, using hydroxocobalamin (OH-Cbl) as a comparative standard. Surface plasmon resonance (SPR) was employed to assess the kinetic parameters of NO-Cbl and OH-Cbl interactions with plant- derived IF across various concentrations. SPR analysis demonstrated that NO-Cbl and OH-Cbl exhibited high binding affinities to IF, with equilibrium dissociation constant (KD) values in the picomolar range. OH-Cbl showed a slightly stronger binding affinity (KD = 4.79 × 10-11 M) than NO-Cbl (KD = 8.58 × 10-11 M). Despite NO-Cbl and OH-Cbl both being bound to IF, differences in binding affinity and stability were observed, particularly at higher concentrations. Variations in IF binding between NO-Cbl and OH-Cbl may be attributed to the saturation of binding sites or recognition issues specific to plant-derived IF. This study underscores the potential of NO-Cbl as a targeted therapeutic agent capable of leveraging natural cobalamin uptake pathways. These results also highlight the suitability of using recombinant plant-derived IF as a model for predicting the biological activity of cobalamin analogs despite the nuanced differences from native human IF.

The human microbiome comprises ∼1013–1014 microbial cells which form a symbiotic relationship with the host and play a critical role in the regulation of human metabolism. In the oral cavity, several species of bacteria are capable of reducing nitrate to nitrite; a key precursor of the signaling molecule nitric oxide. Nitric oxide has myriad physiological functions, which include the maintenance of cardiovascular homeostasis and the regulation of acute and chronic responses to exercise. This article provides a brief narrative review of the research that has explored how diversity and plasticity of the oral microbiome influences nitric oxide bioavailability and related physiological outcomes. There is unequivocal evidence that dysbiosis (e.g. through disease) or disruption (e.g. by use of antiseptic mouthwash or antibiotics) of the oral microbiota will suppress nitric oxide production via the nitrate-nitrite-nitric oxide pathway and negatively impact blood pressure. Conversely, there is preliminary evidence to suggest that proliferation of nitrate-reducing bacteria via the diet or targeted probiotics can augment nitric oxide production and improve markers of oral health. Despite this, it is yet to be established whether purposefully altering the oral microbiome can have a meaningful impact on exercise performance. Future research should determine whether alterations to the composition and metabolic activity of bacteria in the mouth influence the acute responses to exercise and the physiological adaptations to exercise training.