Search Results (47)

Background/Objectives: The non-neuronal cardiac cholinergic system (NNCCS) is known to synthesize ACh independently of the parasympathetic nervous system, thereby regulating cardiac homeostasis, which includes sustainability of energy metabolism, anti-inflammatory and anti-ischemic properties, electrical stability, and mitochondrial calcium handling. Given these beneficial functions of NNCCS, we were prompted to search for an inducer. One such inducer is SNPiP, a novel low-molecular-weight chemical compound developed by us. SNPiP accelerates ACh synthesis in the heart via cGMP elevation and, intriguingly, enhances diastolic function, increasing cardiac output and end-systolic pressure without elevating heart rate. However, the pharmacokinetics of SNPiP remain unknown, which led us to conduct the present study. Methods and Results: We found that the half-life of SNPiP in the blood was extremely short, similar to that of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine. This short half-life is caused by the rapid distribution of SNPiP into organs, including the heart, kidney, and liver. In addition, once transferred into blood cells, SNPiP itself became stable and remained intact for up to 1 h. Moreover, the short half-life was partly explained by the rapid degradation of SNPiP and concomitant loss of the nitroso group in the blood. Notably, when rats were treated with SNPiP, NO levels in the heart elevated bimodally: immediately after administration and again about 12 h later, coinciding with the previous report of NNCCS upregulation and accelerated ACh synthesis with NO production. Importantly, our previous transcriptome analysis of SNPiP-treated hearts supports these findings, as it revealed upregulation of diastolic function-related genes and proteins. Conclusions: Collectively, these results clarify the pharmacokinetics of SNPiP and demonstrate that, despite a shorter half-life, SNPiP is efficiently distributed to the heart, where it confers beneficial effects through induction of NNCCS. Full article

Five new Daphniphyllum alkaloids, daphmacropomines A–E (1–5), were isolated from Daphniphyllum macropodum Miq. and structurally characterized. Compound 1 is an unprecedented Daphniphyllum alkaloid that features a unique 6/9/7/5/5 ring with a rare N-nitroso group. Compound 2 is the second Daphniphyllum alkaloid featuring a highly rearranged 6/6/6/7/5/6-fused skeleton. Compounds 3 and 4 are new yuzurimine-type alkaloids, and their structures were determined by extensive techniques including HRESIMS, NMR, ECD, and single-crystal X-ray. A plausible biosynthetic pathway for 1–4 is proposed. Furthermore, compounds 3 and 4 can induce lysosomal biogenesis and promote autophagic flux. Full article

Cellular senescence (CSEN) is caused by a variety of factors that trigger complex molecular pathways. These include telomere shortening, oncogene activation and replicative stress, as well as DNA damage caused by genotoxic anticancer drugs and endogenous and exogenous genotoxins. Here, we review the induction of CSEN by exogenous genotoxic insults resulting from food and environmental exposures. The available data show that genotoxins/carcinogens in tobacco smoke and smokeless tobacco, in the environment, in food, beverages and life-style products induce CNS. The exposures include N-nitroso compounds, polycyclic aromatic hydrocarbons, heterocyclic aromatic amines, acrylamide, heavy metals, fine dust, mycotoxins, phytotoxins, and phycotoxins. Also, heme in red meat contributes to CSEN as it catalyzes the formation of genotoxic species in the colon. Induction of CSEN by external genotoxins/carcinogens is bound on the DNA damage response pathway (DDR), which relies on activation of the ATM/ATR-CHK2/CHK1-p53-p21 axis and the p53-independent p16/p14 axis, eliciting cyclin-dependent kinase inhibition and permanent cell cycle arrest. Other factors that can be involved are DREAM, MAPK, cGAS/Sting, and NF-κB. The accumulation of non-repaired DNA damage triggering CSEN following external genotoxic exposures may contribute significantly to the amelioration of senescent cells and organ failure with age in humans. Senescent cells drive, via the senescence-associated secretory phenotype (SASP), inflammation that is involved in many diseases, including cancer. Although most of the studies were performed with in vitro cell systems, the consequences of CSEN induction by genotoxic nutritional components and environmental exposures seem to be underestimated. Since CSEN correlates with aging, it is reasonable to conclude that exogenous genotoxic pollutants contribute significantly to the aging process through CSEN induction. In light of these findings, it is deduced that reducing genotoxin exposures and using “rejuvenation” supplements (senotherapeutics) are reasonable strategies to counteract cellular senescence and the aging process. Full article

In this study, atom- and step-efficient electrochemical coupling of nitroso compounds with ammonium N-(methoxy)nitramide, furnishing methoxy-NNO-azoxy compounds, is reported. The developed protocol employs a divided electrochemical cell, proceeds under constant-current electrolysis conditions, and is applicable to aromatic, heterocyclic, and aliphatic nitroso compounds. The versatility of the developed electrochemical coupling method was demonstrated by comparing it with chemical approaches on various substrates. Full article

In this study, the electrochemical coupling of nitrosoarenes with ammonium dinitramide is discovered, leading to the facile construction of the nitro-NNO-azoxy group, which represents an important motif in the design of energetic materials. Compared to known approaches to nitro-NNO-azoxy compounds involving two chemical steps (formation of azoxy group containing a leaving group and its nitration) and demanding expensive, corrosive, and hygroscopic nitronium salts, the presented electrochemical method consists of a single step and is based solely on nitrosoarenes and ammonium dinitramide. The dinitramide salt plays the roles of both the electrolyte and reactant for the coupling. Despite the fact that many side reactions can be expected due to the redox-activity of both the reagents and target products, under optimized conditions the synthesis is performed in an undivided cell under constant current conditions with high current density and can be easily scaled up without a reduction in the product yield. Moreover, the synthesized nitro-NNO-azoxy compounds are discovered to be potent fungicides active against a broad range of phytopathogenic fungi. Full article

Humans are unavoidably exposed to numerous different mutagenic DNA alkylating agents (AAs), but their role in the initiation of cancers is uncertain, in part due to difficulties in assessing human exposure. To address this, we have developed a screening method that measures promutagenic O⁶-alkylguanines (O⁶-AlkGs) in DNA and applied it to human DNA samples. The method exploits the ability of the Schizosaccharomyces pombe alkyltransferase-like protein (Atl1) to recognise and bind to a wide range of O⁶-AlkGs in DNA. We established an Atl1-based slot-blot (ASB) assay and validated it using calf thymus DNA alkylated in vitro with a range of alkylating agents and both calf thymus and human placental DNA methylated in vitro with temozolomide (TMZ). ASB signals were directly proportional to the levels of O⁶-meG in these controls. Pre-treatment of DNA with the DNA repair protein O⁶-methylguanine–DNA methyltransferase (MGMT) reduced binding of Atl1, confirming its specificity. In addition, MCF 10A cells were treated with 500 μM TMZ and the extracted DNA, analysed using the ASB, was found to contain 1.34 fmoles O⁶ -meG/μg DNA. Of six human breast tumour DNA samples assessed, five had detectable O⁶-AlkG levels (mean ± SD 1.24 ± 0.25 O⁶-meG equivalents/μg DNA. This study shows the potential usefulness of the ASB assay to detect and quantify total O⁶-AlkGs in human DNA samples. Full article

Nitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Light-controllable NO releasers show promise in the development of smart therapies. Here, we present a novel biocompatible material based on polydimethylsiloxane (PDMS) doped with BODIPY derivatives containing an N-nitroso moiety that is capable of the photoinduced generation of NO. We study the green-light-induced NO-release properties with the following three methods: electrochemical gas-phase sensor, liquid-phase sensor, and the Griess assay. Prolonged release of NO from the polymer films after short irradiation by narrow-band LED light sources and a laser beam is demonstrated. Importantly, this was accompanied by no or little release of the parent compound (BODIPY-based photodonor). Silicone films with the capability of controllable and clean NO release can potentially be used as a highly portable NO delivery system for different therapeutic applications. Full article

Autoimmune gastritis (AIG) is characterized by the destruction of gastric parietal cells, resulting in hypochlorhydria and eventual achlorhydria, as oxyntic glands in the corpus are destroyed and become atrophic. The permanent loss of gastric acid has many impacts—both theoretical and documented. The most concerning of these are hypergastrinemia and increased N-nitroso compounds, both of which increase the risk of gastric cancers. While known deficiencies of B12 and iron are often replaced in AIG, acid is not. Moreover, patients with AIG are often prescribed acid suppression for a stomach that is decidedly no longer acidic, worsening the sequelae of gastric atrophy. Betaine hydrochloride (BHCL) is a short-acting acidifying agent, available over the counter in capsule form. Mealtime acid supplementation has an historic basis and could ameliorate many AIG-related gastrointestinal symptoms. Theoretically, acidification could also reduce the potential for hypergastrinemia and the production of N-nitroso compounds, consequently reducing the risk of gastric cancers. Supplemental vitamin C may also help in preventing gastric N-nitroso formation, regardless of the gastric pH. This narrative review describes the functions of gastric acid in gastrointestinal and immune health, documents the effects of hypochlorhydria in AIG, and proposes potential options for safely re-establishing the acid milieu of the stomach for patients with AIG. Full article

The PHYTOME study investigated the effect of consuming processed meat products on outcomes related to colorectal cancer risk without testing the impact of genetic variability on these responses. This research aims to elucidate the genetic impact on apparent total N-nitroso compound (ATNC) excretion, colonic DNA adduct formation, ex vivo-induced DNA damage, and gene expression changes in colon biopsies of healthy participants. Through a systematic literature review, candidate polymorphisms were selected and then detected using TaqMan and PCR analysis. The effect of genotype on study outcomes was determined via a linear mixed model and analysis of variance. Machine learning was used to evaluate relative allele importance concerning genotoxic responses, which established a ranking of the most protective alleles and a combination of genotypes (gene scores). Participants were grouped by GSTM1 genotype and differentially expressed genes (DEGs), and overrepresented biological pathways were compared between groups. Stratifying participants by ten relevant genes revealed significant variations in outcome responses. After consumption of processed red meat, variations in NQO1 and COMT impacted responses in ATNC levels (µmol/L) (+9.56 for wildtype vs. heterozygous) and DNA adduct levels (pg/µg DNA) (+1.26 for variant vs. wildtype and +0.43 for variant vs. heterozygous), respectively. After phytochemicals were added to the meat, GSTM1 variation impacted changes in DNA adduct levels (−6.12 for deletion vs. wildtype). The gene scores correlated with these responses and DEGs were identified by GSTM1 genotype. The altered pathways specific to the GSTM1 wildtype group included ‘metabolism’, ‘cell cycle’, ‘vitamin D receptor’, and ‘metabolism of water-soluble vitamins and co-factors’. Genotype impacted both the potential genotoxicity of processed red meat and the efficacy of protective phytochemical extracts. Full article

Endogenously formed N-nitroso compounds (NOCs) from nitrite use in red meat have been recently linked to the risk of colorectal cancer. Therefore, replacing sodium nitrite (E250) with natural antimicrobials, such as bioactive compounds, is an issue of great industrial and scientific interest. In this research, such compounds were extracted from rose petal (Rosa damascena) and rosemary leaf (Rosmarinus officinalis L.) by-products of the essential oil industry and appropriately introduced in commercial cured meat products, as partial nitrite replacers. Shelf-life tests demonstrated an inhibitory effect of the rose extracts on microbial growth, obtaining similar or reduced growth rates and a prolonged lag phase, when compared to conventionally produced samples (CNT): μ_max,ref = 0.128 vs. 0.166 d⁻¹ and λ_ref = 15.9 vs. 12.4 d at 4 °C, respectively. None of the bacon samples suffered from lipid oxidation in the examined period. The RSE samples (containing the rose extract and half of the nitrites) exhibited a good retention of their red color, receiving an acceptable sensory score throughout storage. Since the proposed partial nitrite replacement leads to an important shelf-life extension, namely 78 d (RSE) vs. 60 d (CNT), our results provide preliminary proof of the potential use and valorization of such side streams as effective natural antimicrobial agents for cured meat products, in order to reduce the use of nitrites. Full article

A continuing interest of scientists regarding the development of new β-carotene production technologies is due to the high biological activity of this compound and its wide application range. Bacteria are considered among the possible β-carotene producers convenient for industrial use. The purpose of this study was to develop a Mycolicibacterium neoaurum strain with an enhanced ability for β-carotene production and to optimize the fermentation conditions to improve the final yield of the target compound. Using chemical mutagenesis with N-nitroso-N-methylurea along with further strain selection, a M. neoaurum strain Ac-501/22, whose productivity was 2.7-fold higher than that of the parental strain Ac-501, was developed. The effect of nitrogen and carbon sources as well as cultivation conditions on the growth of M. neoaurum Ac-501/22 and β-carotene production were studied to select the optimal fermentation regime. Due to an increase in the temperature of cultivation from 30 to 35 °C, replacement of glucose with glycerin (20.0 g/L) and degreased soybean flour with powdered milk (10.0 g/L), and increase in the urea content from 0.5 to 1.0 g/L, the level of β-carotene production was improved to 183.0 mg/kg that was 35% higher than in the control. Further strain fermentation in a 3 L bioreactor using an optimized medium with the pH level maintained at 7.0–7.2 and 50% pO₂ provided the maximum output of the target compound (262.4 mg/kg of dry biomass) that confirmed the prospects of the developed strain as an industrial β-carotene producer. Full article

The aim of this work is to highlight the influence of UV light on the hydrolysis reaction of nifedipine (NIF) in the presence of alkaline solutions. In this context, the photodegradation of NIF in the absence of alkaline solutions caused (a) a change in the ratio between the absorbances of three bands in the UV-VIS spectra localized at 224–240 nm, 272–276 nm and 310–340 nm, assigned to the electronic transitions of -COOCH₃ groups, -NO₂ groups and a heterocycle with six atoms; (b) a red-shift of the photoluminescence (PL) band from 458 nm to 477 nm, simultaneous with an increase in its intensity; (c) a decrease in the ratio of the Raman line intensities, which peaked at 1224 cm⁻¹ and 1649 cm⁻¹, associated with the vibrational modes of -C-C-O in the ester group and C=C stretching; and (d) a decrease in the ratio between the absorbances of the IR bands, which peaked at 1493 cm⁻¹ and 1223 cm⁻¹, associated with the vibrational modes of the -NO₂ group and C-N stretching. These changes were explained considering the NIF photodegradation reaction, which leads to the generation of the compound 4-(2-nitrosophenyl)-2.6-dimethyl-3.5-dimethoxy carbonyl pyridine. The interaction of NIF with NaOH in the absence of UV light was demonstrated to induce changes in the vibrational mode of the -C-C-O bond in the ester group. The photodegradation of NIF after its reaction with NaOH induces significant changes highlighted in its (a) UV-VIS spectra, by the shift of the absorption band at 238 nm; (b) PL spectra, by the supraunitary value of the ratio between the emission band intensities at 394–396 nm and 450 nm; (c) Raman spectra, by the change in the ratio between the intensities of the lines that peaked at 1224 cm⁻¹ and 1649 cm⁻¹ from 0.61 to 0.49; and (d) FTIR spectra, by the lowered absorbance of the IR band at 1493 cm⁻¹ assigned to the vibrational mode of the -NO₂ group as a result of the generation of the nitroso compound. These changes were explained considering the hydrolysis reaction products of NIF, as the nitroso compound is converted to a lactam-type compound. The photodegradation reaction rate constants of NIF and NIF after interaction with NaOH were also reported. The decrease in thermal stability of NIF samples after interaction with NaOH, as well as of NIF after exposure to UV light compared to NIF prior to exposure to UV light, was demonstrated by thermogravimetry, and the key fragments were confirmed by mass spectrometry. Full article

N-nitrosamines are a class of carcinogenic chemical compound. Considering the large-scale application of agrochemicals globally, the elimination of N-nitrosamines from pesticides should be a priority for manufacturers and regulators. A set of methods was developed and validated for the determination of the toxicologically relevant N-nitrosamine impurity of ethalfluralin (ethyl-N-(2-methylallyl) N-nitroso amine—EMANA) in 33% w v⁻¹ emulsifiable concentrate (EC) formulations. Solid Phase Extraction (SPE) was compared with the “dilute and shoot” approach. Gas chromatography (GC) was combined with Flame Ionization Detection (FID) and mass spectrometry (MS). For MS, two mass filtering modes (Selective Ion Monitoring—SIM, tandem mass spectrometry—MS/MS) and two ionization modes (Electron Ionization—EI, Positive chemical ionization—PCI) were applied. It was concluded that, in the case of samples with high nitrosamine concentration (>90 μg g⁻¹), the “dilute and shoot” approach can be applied without compromising the quality of the results. SPE, however, is required to attain the LOQ (0.33 μg g⁻¹) with good recovery (97.4–110.67%), linearity (R > 0.99) and precision (%RSD 0.68–1.74). The LOQ supersedes the limit set by EFSA (1 μg g⁻¹) in the Technical Active Substance—TAS. The concentration range of the methods is 0.05–110 μg g⁻¹. The methods were applied for the official surveillance program of the Greek agrochemicals market. Full article

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4H-1,2-oxazine N-oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2H-[1,2]oxazino[2,3-b][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in THF at room temperature, which allows the preparation of target products in good yields and excellent diastereoselectivity. Under basic conditions, namely, the combined action of DBU and alcohol, these nitroso acetals undergo ring contraction of an unsaturated oxazine ring into the corresponding pyrrole. Both transformations can be performed in a one-pot fashion, thus constituting a quick approach to oxazine-annulated pyrroles from available starting materials, such as nitroalkenes, olefins, and diazo compounds. Full article