The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with periodontal health, but the impact of periodontitis on nitrate-reducing capacity (NRC) and, therefore, nitric oxide availability has not been evaluated. The current study aimed to evaluate how periodontitis affects the NRC of the oral microbiota. First, 16S rRNA sequencing data from five different countries were analyzed, revealing that nitrate-reducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals (P < 0.05 in all five datasets with n = 20-82 samples per dataset). Secondly, subgingival plaque, saliva, and plasma samples were obtained from 42 periodontitis patients before and after periodontal treatment. The oral NRC was determined in vitro by incubating saliva with 8 mmol/L nitrate (a concentration found in saliva after nitrate-rich vegetable intake) and compared with the NRC of 15 healthy individuals. Salivary NRC was found to be diminished in periodontal patients before treatment (P < 0.05) but recovered to healthy levels 90 days post-treatment. Additionally, the subgingival levels of nitrate-reducing bacteria increased after treatment and correlated negatively with periodontitis-associated bacteria (P < 0.01). No significant effect of periodontal treatment on the baseline saliva and plasma nitrate and nitrite levels was found, indicating that differences in the NRC may only be revealed after nitrate intake. Our results suggest that an impaired NRC in periodontitis could limit dietary nitrate-derived nitric oxide levels, and the effect on systemic health should be explored in future studies.
Humans ; Nitrates ; Nitric Oxide ; Nitrites ; RNA, Ribosomal, 16S/genetics* ; Periodontitis/microbiology* ; Bacteria ; Dental Plaque/microbiology* ; Saliva/microbiology* ; Microbiota/genetics*

Humans ; Nitric Oxide ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms ; Lung ; Nitric Oxide Synthase ; Macrophages, Alveolar ; Pulmonary Alveoli

Long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4) is an enzyme that esterifies CoA into specific polyunsaturated fatty acids, such as arachidonic acid and adrenic acid. Based on accumulated evidence, the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to the execution of ferroptosis by triggering phospholipid peroxidation. Ferroptosis is a type of programmed cell death caused by iron-dependent peroxidation of lipids; ACSL4 and glutathione peroxidase 4 positively and negatively regulate ferroptosis, respectively. In addition, ACSL4 is an essential regulator of fatty acid (FA) metabolism. ACSL4 remodels the phospholipid composition of cell membranes, regulates steroidogenesis, and balances eicosanoid biosynthesis. In addition, ACSL4-mediated metabolic reprogramming and antitumor immunity have attracted much attention in cancer biology. Because it facilitates the cross-talk between ferroptosis and FA metabolism, ACSL4 is also a research hotspot in metabolic diseases and ischemia/reperfusion injuries. In this review, we focus on the structure, biological function, and unique role of ASCL4 in various human diseases. Finally, we propose that ACSL4 might be a potential therapeutic target.
Humans ; Ferroptosis ; Apoptosis ; Phospholipids/metabolism* ; Nitric Oxide Synthase

Uric acid (UA) is the final product of purine metabolism in human body,and its metabolic disorder will induce hyperuricemia (HUA).The occurrence and development of HUA are associated with a variety of pathological mechanisms such as oxidative stress injury,activation of inflammatory cytokines,and activation of renin-angiotensin-aldosterone system.These mechanisms directly or indirectly affect the bioavailability of endogenous nitric oxide (NO).The decrease in NO bioavailability is common in the diseases with high concentration of UA as an independent risk factor.In this review,we summarize the mechanisms by which high concentrations of UA affect the endogenous NO bioavailability,with a focus on the mechanisms of high-concentration UA in decreasing the synthesis and/or increasing the consumption of NO.This review aims to provide references for alleviating the multisystem symptoms and improving the prognosis of HUA,and lay a theoretical foundation for in-depth study of the correlations between HUA and other metabolic diseases.
Humans ; Nitric Oxide ; Uric Acid ; Hyperuricemia ; Biological Availability ; Cytokines

OBJECTIVE: To investigate the anti-oxidant and anti-inflammatory effects of ethanol extract of Polygala sibirica L. var megalopha Fr. (EEP) on RAW264.7 mouse macrophages. METHODS: RAW264.7 cells were pretreated with 0-200 µg/mL EEP or vehicle for 2 h prior to exposure to 1 µg/mL lipopolysaccharide (LPS) for 24 h. Nitric oxide (NO) and prostaglandin (PGE₂) production were determined by Griess reagent and enzyme-linked immunosorbent assay (ELISA), respectively. The mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin-1beta (IL-1β), and IL-6 were determined using reverse transcription polymerase chain reaction (RT-PCR). Western blot assay was used to determine the protein expressions of iNOS, COX-2, phosphorylation of extracellular regulated protein kinases (ERK1/2), c-Jun N-terminal kinase (JNK), inhibitory subunit of nuclear factor Kappa B alpha (Iκ B-α) and p38. Immunofluorescence was used to observe the nuclear expression of nuclear factor-κ B p65 (NF-κ B p65). Additionally, the anti-oxidant potential of EEP was evaluated by reactive oxygen species (ROS) production and the activities of catalase (CAT) and superoxide dismutase (SOD). The 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), superoxide anion (O₂^-) radical and nitrite scavenging activity were also measured. RESULTS: The total polyphenol and flavonoid contents of EEP were 23.50±2.16 mg gallic acid equivalent/100 g and 43.78±3.81 mg rutin equivalent/100 g. With EEP treatment (100 and 150 µg/mL), there was a notable decrease in NO and PGE₂ production induced by LPS in RAW264.7 cells by downregulation of iNOS and COX-2 mRNA and protein expressions (P<0.01 or P<0.05). Furthermore, with EEP treatment (150 µg/mL), there was a decrease in the mRNA expression levels of TNF-α, IL-1β and IL-6, as well as in the phosphorylation of ERK, JNK and p38 mitogen-activated protein kinase (MAPK, P<0.01 or P<0.05), by blocking the nuclear translocation of NF-κ B p65 in LPS-stimulated cells. In addition, EEP (100 and 150 µg/mL) led to an increase in the anti-oxidant enzymes activity of SOD and CAT, with a concomitant decrease in ROS production (P<0.01 or P<0.05). EEP also indicated the DPPH, OH, O₂^- radical and nitrite scavenging activity. CONCLUSION EEP inhibited inflammatory responses in activated macrophages through blocking MAPK/NF-κ B pathway and protected against oxidative stress.
Animals ; Mice ; Antioxidants/pharmacology* ; Lipopolysaccharides/pharmacology* ; Polygala ; Transcription Factor RelA/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Ethanol/chemistry* ; Interleukin-6/metabolism* ; Anti-Inflammatory Agents/chemistry* ; Reactive Oxygen Species/metabolism* ; Cyclooxygenase 2/metabolism* ; Nitrites/metabolism* ; NF-kappa B/metabolism* ; Nitric Oxide/metabolism* ; Superoxide Dismutase/metabolism* ; RNA, Messenger ; Nitric Oxide Synthase Type II/metabolism*

In the central nervous system, nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS). In the past 20 years, the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders. In particular, the interactions between the PDZ domain of nNOS and its adaptor proteins, including post-synaptic density 95, the carboxy-terminal PDZ ligand of nNOS, and the serotonin transporter, significantly influence the subcellular localization and functions of nNOS in the brain. The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders. Here, we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.
Humans ; Nitric Oxide Synthase Type I/metabolism* ; Adaptor Proteins, Signal Transducing ; Brain/metabolism* ; Nervous System Diseases

We reported the discovery of six novel coumarins, toddasirins A-F (1-6), each endowed with modified isoprenyl or geranyl side chains, derived from the roots of Toddalia asiatica. Comprehensive structural elucidation was achieved through multispectroscopic analyses, single-crystal X-ray diffraction experiments, and advanced quantum mechanical electronic circular dichroism (ECD) calculations. Furthermore, the anti-inflammatory activity of these compounds was assessed. Notably, compounds 1-3 and 6 demonstrated notable inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells, with 50% inhibitory concentration (IC₅₀) values of 3.22, 4.78, 8.90, and 4.31 μmol·L^-1, respectively.
Mice ; Animals ; Coumarins/chemistry* ; Rutaceae/chemistry* ; Anti-Inflammatory Agents/pharmacology* ; Plant Extracts/chemistry* ; RAW 264.7 Cells ; Nitric Oxide ; Molecular Structure

Five new racemic N-acetyldopamine (NADA) trimers, asponchimides A-E (1-5), were isolated from Aspongopus chinensis, a prominent traditional Chinese medicinal insect employed for alleviating pain, treating indigestion, and addressing kidney ailments. Compounds 1-5 were successfully resolved by chiral high-performance liquid chromatography (HPLC), yielding five pairs of enantiomers: (+)- and (-)-asponchimides A-E (1a/1b-5a/5b). Their structural identities were discerned by extensive spectroscopic analyses, including high-resolution mass spectrometry (HRMS), ultraviolet-visible (UV-Vis) spectroscopy, infrared (IR) spectroscopy, and nuclear magnetic resonance (NMR), and their absolute configurations were determined by electronic circular dichroism (ECD) calculations. Compounds 1-5 are pioneering instances of NADA trimers featuring a Δ⁷ double bond. When subjected to a series of bioassays, a majority of the compounds exhibited weak inhibitory activity against nitric oxide (NO) production in LPS-induced RAW 264.7 cells.
Molecular Structure ; Magnetic Resonance Spectroscopy ; Dopamine ; Nitric Oxide

Natural products are essential sources of antitumor drugs. One such molecule, β-elemene, is a potent antitumor compound extracted from Curcuma wenyujin. In the present investigation, a series of novel 13,14-disubstituted nitric oxide (NO)-donor β-elemene derivatives were designed, with β-elemene as the foundational compound, and subsequently synthesized to evaluate their therapeutic potential against leukemia. Notably, the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line, with a high NO release. In vivo studies indicated that compound 13d could effectively inhibit tumor growth, exhibiting no discernible toxic manifestations. Specifically, a significant tumor growth inhibition rate of 62.9% was observed in the K562 xenograft tumor mouse model. The accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia.
Humans ; Mice ; Animals ; Cell Line, Tumor ; Nitric Oxide Donors/pharmacology* ; Sesquiterpenes/pharmacology* ; Leukemia/drug therapy* ; Biological Assay ; Cell Proliferation

Objective: To investigate the clinical characteristics of Aspergillus fumigatus(A.f)-sensitized asthma and allergic bronchopulmonary aspergillosis (ABPA), which provides a foundation for the diagnosis and differential diagnosis of A.f-sensitized asthma and ABPA, as well as the prevention of ABPA. Methods: This was a single-center retrospective case-control study. Collected the clinical data of patients who visited the Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University from December 2018 to May 2022.A total of 122 patients were included, including 64 males (52.5%) and 58 females (47.5%).The age range was 3 to 89 years.The median age was 44 years.The average age was 41.8 years.The patients were divided into three groups (48 ABPA, 35 A.f-sensitized asthma and 39 HDM-sensitized asthma).Analyzed the differences and correlations among clinical indicators in the three groups, and evaluated the risk factors for the development of ABPA in A.f-sensitized asthma.For statistical analysis, metrological data was tested by t-test or Wilcoxon Mann-Whitney. Classification variables by chi-square test or Fisher's exact test. Pearson correlation analysis for normal distribution data.Spearman correlation analysis for skewed distribution data. Influencing factor analysis was performed using multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve was made, the area under the ROC curve (AUC) was calculated, and the sensitivity and specificity of the model were evaluated. Results: Compared with patients with A.f-sensitized asthma, the fractional exhaled nitric oxide (FeNO) [75.00(52.00, 87.00)ppb vs. 40.00(32.00, 52.00)ppb], eosinophils% (EO%) [10.60(6.75, 13.05) vs. 4.10(1.20, 7.30)], eosinophils (EO) [1.50(1.07, 2.20)×10⁹/L vs. 0.33(0.10, 0.54)×10⁹/L], A.f-specific Immunoglobulin E (sIgE) [10.24(4.09, 22.88)KU/L vs. 1.13(0.53, 3.72) KU/L], and sIgE to total IgE(tIgE) ratio (sIgE/tIgE) [0.0049(0.0027, 0.0100) vs. 0.0008(0.0004, 0.0017)] were higher in ABPA patients, the differences were statistically significant (P<0.001). In all patients, tIgE was positively correlated with EO% (r=0.206, P<0.05) and EO (r=0.302, P<0.001). sIgE/tIgE was negatively correlated with one-second rate (FEV1/FVC%) (r=-0.256, P<0.01). The percentage of predicted forced vital capacity [FVC(%)] was negatively correlated with FeNO (r=-0.184, P<0.05).In the ABPA group, the percentage of predicted peak expiratory flow [PEF(%)] was negatively correlated with FeNO (r=-0.295, P<0.05). In the HDM-sensitized asthma group, FeNO was positively correlated with EO% (r=0.49, P<0.01) and EO (r=0.548, P<0.001).The results of logistic regression analysis showed that FeNO and EO were the influencing factors for the development of ABPA in A.f-sensitized asthma. ROC curve analysis results showed that A.f-sIgE (cut-off, 4.108; AUC=0.749;95%CI, 0.632-0.867), sIgE/tIgE(cut-off, 0.0026;AUC=0.749;95%CI, 0.631-0.868), FeNO(cut-off, 55.5;AUC=0.794; 95%CI, 0.687-0.900), EO% (cut-off, 8.70;AUC=0.806;95%CI, 0.709-0.903) and EO (cut-off, 0.815;AUC=0.865;95%CI, 0.779-0.950) had differential diagnostic value in A.f-sensitized asthma and ABPA.The combination of FeNO, EO and EO% had good diagnostic efficiency in differentiating A.f-sensitized asthma from ABPA, with a sensitivity of 91.4% and a specificity of 84.4%. Conclusion: Compared with patients with A.f-sensitized asthma, patients with ABPA have more severe eosinophil inflammation. The higher the FeNO and EO, the more likely A.f-sensitized asthma will develop into ABPA.sIgE/tIgE may have differential diagnostic value in A.f-sensitized asthma and ABPA.The combination of FeNO, EO and EO% has good diagnostic efficacy in differentiating A.f-sensitized asthma from ABPA.
Male ; Female ; Humans ; Adult ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Aspergillus fumigatus ; Retrospective Studies ; Case-Control Studies ; Aspergillosis, Allergic Bronchopulmonary/diagnosis* ; Asthma/diagnosis* ; Immunoglobulin E ; Nitric Oxide