Confirmation of N-(Nitrosomethyl) urea as a Nitrosourea Derived by Nitrosation of Fish Sauce

N-(nitrosomethyl ) urea (NMU ) was characterized in the carcinogenic nitrosated fish sauce (NFS) with high performance liquid chromatography (HPLC )- pholohydrolysis-pyrolysis-thermal en -ergy analysis recently. We used HPLC-electronic spray ionization-mass spectrometry and HPLC-diode array detection to confirm NMU in NFS furiher. It was observed that the corresponding chro-matographic fraction of NMU of NFS showed the same mass spectrum (m/z 64, 102, and 145) andultraviolet-absorbance (λ max = 230 nm) as those of authentic NMU. These results confirmed that thecomponent of NFS was NMU

Competitive metabolism of L-arginine:arginase as a therapeutic target in asthma

Exhaled breath nitric oxide （NO） is an accepted asthma biomarker. Lung concentrations of NO and its amino acid precursor, L-arginine, are regulated by the relative expressions of the NO synthase （NOS） and arginase isoforms. Increased expression of arginase I and NOS2 occurs in murine models of allergic asthma and in biopsies of asthmatic airways. Although clinical trials involving the inhibition of NO-producing enzymes have shown mixed results, small molecule arginase inhibitors have shown potential as a therapeutic intervention in animal and cell culture models. Their transition to clinical trials is hampered by concerns regarding their safety and potential tox- icity. In this review, we discuss the paradigm of arginase and NOS competition for their substrate L-arginine in the asthmatic airway. We address the functional role of L-arginine in inflammation and the potential role of arginase inhibitors as therapeutics.

New solutions for old challenges in glaucoma treatment:is taurine an option to consider?

Glaucoma is a range of progressive optic neuropathies characterized by progressive retinal ganglion cell loss and visual field defects.It is recognized as a leading cause of irreversible blindness affecting more than 70 million people worldwide.Currently,reduction of intraocular pressure,a widely recognized risk factor for glaucoma development,is the only pharmacological strategy for slowing down retinal ganglion cell loss and disease progression.However,retinal ganglion cell death and visual field loss have been observed in normotensive glaucoma,suggesting that the disease process is partially independent of intraocular pressure.Taurine is one of the agents that have attracted attention of researchers recently.Taurine has been shown to be involved in multiple cellular functions,including a central role as a neurotransmitter,as a trophic factor in the central nervous system development,as an osmolyte,as a neuromodulator,and as a neuroprotectant.It also plays a role in the maintenance of the structural integrity of the membranes and in the regulation of calcium transport and homeostasis.Taurine is known to prevent N-methyl-D-aspartic acid-induced excitotoxic injury to retinal ganglion cells.A recently published study clearly demonstrated that taurine prevents retinal neuronal apoptosis both in vivo and in vitro.Protective effect of taurine may be attributed to direct inhibition of apoptosis,an activation of brain derived neurotrophic factor-related neuroprotective mechanisms and reduction of retinal oxidative and nitrosative stresses.Further studies are needed to fully explore the potential of taurine as a neuroprotective agent,so that it can be applied in clinical practice,particularly for the treatment of glaucoma.The objective of current review was to summarize recent evidence on neuroprotective properties of taurine in glaucoma.

False dogmas in mood disorders research:Towards a nomothetic network approach

The current understanding of major depressive disorder(MDD)and bipolar disorder(BD)is plagued by a cacophony of controversies as evidenced by competing schools to understand MDD/BD.The DSM/ICD taxonomies have cemented their status as the gold standard for diagnosing MDD/BD.The aim of this review is to discuss the false dogmas that reign in current MDD/BD research with respect to the new,data-driven,machine learning method to model psychiatric illness,namely nomothetic network psychiatry(NNP).This review discusses many false dogmas including:MDD/BD are mind-brain disorders that are best conceptualized using a bio-psycho-social model or mind-brain interactions;mood disorders due to medical disease are attributable to psychosocial stress or chemical imbalances;DSM/ICD are the gold standards to make the MDD/BD diagnosis;severity of illness should be measured using rating scales;clinical remission should be defined using threshold values on rating scale scores;existing diagnostic BD boundaries are too restrictive;and mood disorder spectra are the rule.In contrast,our NNP models show that MDD/BD are not mind-brain or psycho-social but systemic medical disorders;the DSM/ICD taxonomies are counterproductive;a shared core,namely the reoccurrence of illness(ROI),underpins the intertwined recurrence of depressive and manic episodes and suicidal behaviors;mood disorders should be ROI-defined;ROI mediates the effects of nitro-oxidative stress pathways and early lifetime trauma on the phenome of mood disorders;severity of illness and treatment response should be delineated using the NNP-derived causome,pathway,ROI and integrated phenome scores;and MDD and BD are the same illness.

Association of non-alcoholic fatty liver disease and COVID-19: A literature review of current evidence

The coronavirus disease 2019(COVID-19)pandemic has swept through nations,crippled economies and caused millions of deaths worldwide.Many people diagnosed with COVID-19 infections are often found to develop liver injury,which,in a small portion of patients,progresses to severe liver disease.Liver injury in the form of elevated transaminases,hyperbilirubinemia and alterations in serum albumin has been observed to be higher in patients with severe forms of the disease.Those who already have insult to the liver from chronic disease,such as nonalcoholic fatty liver disease(NAFLD)may be at the greatest disadvantage.The severity of COVID-19 also seems to be driven by the presence of NAFLD and other co-morbidities.About 25%of the global population has NAFLD.With such a widespread prevalence of NAFLD,understanding the disease progression of COVID-19 and the occurrence of liver injury in this vulnerable population assumes great significance.In this review,we present an overview of COVID-19 infection in patients with NAFLD.

The endocannabinoid system： ＇NO＇ longer anonymous in the control of nitrergic signalling？

The endocannabinoid system （ECS） is a key cellular signalling system that has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule, which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS-mediated regulation of nitric oxide production, as well as the involvement of reactive nitrogen species in regulating ECS-induced signal transduction by highlighting emerging work support- ing nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic sig- nalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homoeostasis and contribute to vari- ous pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS-nitric oxide signalling axis in disease development and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular, and metabolic disorders.

Redox regulation of the immune response

The immune-inflammatory response is associated with increased nitro-oxidative stress.The aim of this mechanistic review is to examine:(a)the role of redox-sensitive transcription factors and enzymes,ROS/RNS production,and the activity of cellular antioxidants in the activation and performance of macrophages,dendritic cells,neutrophils,T-cells,B-cells,and natural killer cells;(b)the involvement of high-density lipoprotein(HDL),apolipoprotein A1(ApoA1),paraoxonase-1(PON1),and oxidized phospholipids in regulating the immune response;and(c)the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response.The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor-κB,HIF1α,the mechanistic target of rapamycin,the phosphatidylinositol 3-kinase/protein kinase B signaling pathway,mitogen-activated protein kinases,5'AMP-activated protein kinase,and peroxisome proliferator-activated receptor.The performance and survival of individual immune cells is under redox control and depends on intracellular and extracellular levels of ROS/RNS.They are heavily influenced by cellular antioxidants including the glutathione and thioredoxin systems,nuclear factor erythroid 2-related factor 2,and the HDL/ApoA1/PON1 complex.Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems,the tricarboxylic acid cycle,mitochondrial functions,and the metabolism of immune cells.In conclusion,redox-associated mechanisms modulate metabolic reprogramming of immune cells,macrophage and T helper cell polarization,phagocytosis,production of pro-versus anti-inflammatory cytokines,immune training and tolerance,chemotaxis,pathogen sensing,antiviral and antibacterial effects,Toll-like receptor activity,and endotoxin tolerance.

Nitrosative stress in human spermatozoa causes cell death characterized by induction of mitochondrial permeability transition-driven necrosis

Peroxynitrite is a highly reactive nitrogen species and a potent inducer of apoptosis and necrosis in somatic cells. Peroxynitrite-induced nitrosative stress has emerged as a major cause of impaired sperm function; however, its ability to trigger cell death has not been described in human spermatozoa. The objective here was to characterize biochemical and morphological features of cell death induced by peroxynitrite-mediated nitrosative stress in human spermatozoa. For this, spermatozoa were incubated with and without （untreated control） 3-morpholinosydnonimine （SIN-l）, in order to generate peroxynitrite. Sperm viability, mitochondrial permeability transition （MPT）, externalization of phosphatidylserine, DNA oxidation and fragmentation, caspase activation, tyrosine nitration, and sperm ultrastructure were analyzed. The results showed that at 24 h of incubation with SIN-l, the sperm viability was significantly reduced compared to untreated control （P〈 0.001）. Furthermore, the MPT was induced （P〈 0.01） and increment in DNA oxidation （P 〈 0.01）, DNA fragmentation （P 〈 0.01）, tyrosine nitration （P 〈 0.0001） and ultrastructural damage were observed when compared to untreated control. Caspase activation was not evidenced, and although phosphatidylserine externalization increased compared to untreated control （P 〈 0.001）, this process was observed in 〈10% of the cells and the gradual loss of viability was not characterized by an important increase in this parameter. In conclusion, peroxynitrite-mediated nitrosative stress induces the regulated variant of cell death known as MPT-driven necrosis in human spermatozoa. This study provides a new insight into the pathophysiology of nitrosative stress in human spermatozoa and opens up a new focus for developing specific therapeutic strategies to better preserve sperm viability or to avoid cell death.

Cumulative damage by nonthermal plasma exceeds the defense barrier of multiple antibiotic-resistant Staphylococcus aureus: a key to achieve complete inactivation

Objectives:The aim of this study was to provide a comprehensive understanding of the nonthermal plasma(NTP)-induced inactivated behaviors on a multiple antibiotic-resistant(MAR)Staphylococcus aureus(S.aureus).Materials and Methods:A dielectric barrier discharge(DBD)NTP system was employed for the inactivation of a MAR S.aureus under various applied powers of 35,45,and 55 W,and gas distances of 4,6,and 8 mm.The inactivation kinetics of S.aureus were estimated with linear and nonlinear predictive models.In addition,degradation of carotenoid pigment,peroxidation of fatty acids,oxidation of nucleic acids and proteins,and alteration in gene expression were analyzed after NTP treatment.Results and Discussion:The computationally simulated results indicated that the densities of various reactive species increased with enhanced applied powers and decreased discharge distances.These species were further transformed into reactive oxidative and nitrogen species in the gas-liquid interphase and liquid phase.The oxidative and nitrosative stress of NTP resulted in severe damage to cellular components and the morphological structure of S.aureus.On the other hand,the plasma reactive species could also induce the sublethal injury of S.aureus through upregulating the general stress response,antioxidative and antinitrosative defensive systems.Once the cumulative damages overrode the stress tolerance of S.aureus,the completed cell death was finally achieved by NTP.Conclusions:This work infers the possible risk of inducing the repair and resistant capacity of pathogens when the applied NTP parameters are inappropriate,which helps the optimization of NTP process to achieve sufficient inactivation.

MiADMSA minimizes arsenic induced bone degeneration in Sprague Dawley rats

Arsenic considered as one of the most hazardous chemical while arsenic poisoning is also one of the serious medical issues worldwide.Long term arsenic exposure is associated with bone degeneration.The exact mechanism involving arsenic induced bone degeneration remains unclear but,plentiful literature suggested that oxidative/nitrosative stress caused by generation of reactive oxygen species(ROS)and reactive nitrogen species(RNS)is one of the leading causes.Various treatment strategies are available for bone degeneration however,the suitable treatment for arsenic induced bone degeneration still lacks.In the current investigation,we evaluated the efficacy of chelation against arsenic induced bone degeneration in experimental rats.Male Sprague Dawley rats were exposed to sodium arsenite and dimethylarsinic acid(DMA)(50 ppm)for 18 weeks.After arsenic exposure,animals were treated with Monoisoamyl dimercaptosuccinic acid(MiADMSA)for three course of treatment(50 mg/kg,p.o.,once daily for 5 days)with an interval of one week between two courses of treatment.MiADMSA minimizes the bone degeneration through reduction of oxidative stress(Reactive Oxygen Species,Reactive Nitrogen Species,and thiobarbituric reactive substances),alteration of antioxidant status(rGSH,Superoxide dismutase,Catalase)which led to the depletion in the levels of inflammatory markers like TNFa and IL-1b and alteration in the bone remodelling biomarkers like ALP,RANKL,and Runx2.It can be concluded from this study that MiADMSA could be an effective therapeutic strategy against arsenic induced bone degeneration and the possible mechanism could be the chelation of arsenic accompanied by the reduction in oxidative stress and inflammation.