Low Levels Of NO Research Articles

Evaluation of muscular apoptotic changes and myogenin gene expression in experimental trichinosis after stem cells and atorvastatin added to ivermectin treatment

Trichinosis is a common parasitic disease that affects the striated skeletal muscles, causing apoptotic and degenerative changes associated with myogenin expression in the affected myocytes. Hence, this study aimed to assess the ameliorative effects of stem cells and atorvastatin added to ivermectin on the infected myocytes during the muscular phase of murine trichinosis. 120 laboratory Swiss albino male mice were divided into 10 groups, and each group was subdivided into intestinal and muscular phases (each n = 6); uninfected control; untreated infected control; infected received ivermectin monotherapy; infected received atorvastatin monotherapy; infected received stem cells monotherapy; infected received ivermectin and atorvastatin dual therapy; infected received ivermectin and stem cells dual therapy; infected received atorvastatin and stem cells dual therapy; infected received ivermectin 0.2, atorvastatin 40, and stem cells triple therapy; and infected received ivermectin 0.1, atorvastatin 20, and stem cells triple therapy. Intestinal phase mice were sacrificed on the 5th day post-infection, while those of the muscular phase were sacrificed on the 35th day post-infection. Parasitological, histopathological, ultrastructural, histochemical, biochemical, and myogenin gene expression assessments were performed. The results revealed that mice that received ivermectin, atorvastatin, and stem cell triple therapies showed the maximum reduction in the adult worm and larvae burden, marked improvement in the underlying muscular degenerative changes (as was noticed by histopathological, ultrastructural, and histochemical Feulgen stain assessment), lower biochemical levels of serum NK-κB and tissue NO, and lower myogenin expression. Accordingly, the combination of stem cells, atorvastatin, and ivermectin affords a potential synergistic activity against trichinosis with considerable healing of the underlying degenerative sequel.

NOS2-derived low levels of NO drive psoriasis pathogenesis

Psoriasis is an IL-23/Th17-mediated skin disorder with a strong genetic predisposition. The impact of its susceptibility gene nitric oxide synthase 2 (NOS2) remains unknown. Here, we demonstrate strong NOS2 mRNA expression in psoriatic epidermis, an effect that is IL-17 dependent. However, its complete translation to protein is prevented by the IL-17-induced miR-31 implying marginally upregulated NO levels in psoriatic skin. We demonstrate that lower levels of NO, as opposed to higher levels, increase keratinocyte proliferation and mediate IL-17 downstream effects. We hypothesized that the psoriatic phenotype may be alleviated by either eliminating or increasing cellular NO levels. In fact, using the imiquimod psoriasis mouse model, we found a profound impact on the psoriatic inflammation in both IMQ-treated NOS2 KO mice and wild-type mice treated with IMQ and the NO-releasing berdazimer gel. In conclusion, we demonstrate that IL-17 induces NOS2 and fine-tunes its translation towards a window of proinflammatory and hyperproliferative effects and identify NO donor therapy as a new treatment modality for psoriasis.

Associations of neighbourhood attributes with depression in mid-age and older adults: the moderating role of traffic-related air pollution and neighbourhood socioeconomic status

ABSTRACT We aimed to examine whether features of the natural, built and socioeconomic neighbourhood environments were related to depressive symptoms in Australian mid-age and older adults; and whether traffic-related air pollution (TRAP) (NO2) and area-level SES moderated the associations. A total of 4141 of participants (M age = 61 years) were included in this cross-sectional study. Neighbourhood environmental characteristics included percentages of parkland, blue space and commercial land use, population density (persons/hectare), street intersection density (intersections/km2) within 1 km residential buffers. Annual mean concentrations of nitrogen dioxide (NO2) were included. In total-effect models, greater street intersection connectivity was associated with fewer depressive symptoms. Population density was positively associated with depressive symptoms in direct-effect models. Residents from disadvantaged areas with low levels of NO2 and with greater commercial land use coverage reported fewer depressive symptoms. In contrast, residents were more likely to report depressive symptoms with greater coverage of commercial land use in high SES neighbourhoods with low levels of NO2. Street connectivity and population density play a role in the maintenance of mental health in older adults. NO2 and area-level SES are moderators of commercial land use-depression associations, and this knowledge can better inform planning of commercial destinations and facilities in urban environments.

INOS regulates hematopoietic stem and progenitor cells via mitochondrial signaling and is critical for bone marrow regeneration

Hematopoietic stem cells (HSCs) replenish blood cells under steady state and on demand, that exhibit therapeutic potential for Bone marrow failures and leukemia. Redox signaling plays key role in immune cells and hematopoiesis. However, the role of reactive nitrogen species in hematopoiesis remains unclear and requires further investigation. We investigated the significance of inducible nitric oxide synthase/nitric oxide (iNOS/NO) signaling in hematopoietic stem and progenitor cells (HSPCs) and hematopoiesis under steady-state and stress conditions. HSCs contain low levels of NO and iNOS under normal conditions, but these increase upon bone marrow stress. iNOS-deficient mice showed subtle changes in peripheral blood cells but significant alterations in HSPCs, including increased HSCs and multipotent progenitors. Surprisingly, iNOS-deficient mice displayed heightened susceptibility and delayed recovery of blood progeny following 5-Fluorouracil (5-FU) induced hematopoietic stress. Loss of quiescence and increased mitochondrial stress, indicated by elevated MitoSOX and MMPhi HSCs, were observed in iNOS-deficient mice. Furthermore, pharmacological approaches to mitigate mitochondrial stress rescued 5-FU-induced HSC death. Conversely, iNOS-NO signaling was required for demand-driven mitochondrial activity and proliferation during hematopoietic recovery, as iNOS-deficient mice and NO signaling inhibitors exhibit reduced mitochondrial activity. In conclusion, our study challenges the conventional view of iNOS-derived NO as a cytotoxic molecule and highlights its intriguing role in HSPCs. Together, our findings provide insights into the crucial role of the iNOS–NO–mitochondrial axis in regulating HSPCs and hematopoiesis.

Identification of O3 Sensitivity to Secondary HCHO and NO2 Measured by MAX-DOAS in Four Cities in China

This study analyzed the differences in ozone (O3) sensitivity in four different urban areas in China from February 2019 to January 2020 based on data on various near-surface pollutants from passive multi-axis differential optical absorption spectroscopy (MAX-DOAS) sites and nearby China National Environmental Monitoring Center (CNEMC) sites. Across the four cities, the nitrogen dioxide (NO2) and formaldehyde (HCHO) concentrations varied seasonally. Xianghe consistently displayed the lowest NO2 levels, suggesting reduced emissions compared to other cities. Guangzhou, a city with a robust economy and a high level of vehicle ownership, exhibited higher concentrations in spring. Summer brought elevated HCHO levels in Guangzhou, Xianghe, and Shenyang due to intensified photochemical processes. Autumn and winter showed higher HCHO concentrations in Guangzhou and Xianghe compared to Lanzhou and Shenyang. Overall, Guangzhou recorded the highest annual averages, due to its developed economy, while Xianghe’s lower NO2 levels were offset by the elevated HCHO due to higher O3 values. The analysis delved into primary and secondary HCHO sources across seasons and used carbon monoxide (CO) and O3 data. Xianghe showcased the dominance of secondary sources in summer and autumn, while Lanzhou was characterized by primary dominance throughout the year. Shenyang mirrored Xianghe’s evolution due to industrial emissions. In Guangzhou, due to the high levels of vehicular traffic and sunlight conditions, secondary sources predominantly influenced HCHO concentrations. These findings highlight the interplay between primary and secondary emissions in diverse urban settings. This study explored O3 sensitivity variations across seasons. Xianghe exhibited a balanced distribution among volatile organic compound (VOC)-limited conditions, nitrogen oxide (NOx)-limited conditions, and transitional influences. Lanzhou was mainly affected by VOC-limited conditions in winter and NOx-limited conditions in other seasons. Shenyang’s sensitivity varied with the seasons and was primarily influenced by transitions between VOCs and NOx in autumn and NOx-limited conditions otherwise. Guangzhou experienced varied influences. During periods of high O3 pollution, all regions were affected by NOx-limited conditions, indicating the necessity of NOx monitoring in these areas, especially during summer in all regions and during autumn in Xianghe and Guangzhou.

Lactate thresholds and role of nitric oxide in male rats performing a test with forced swimming to exhaustion.

The present study assessed a complex of biochemical parameters at the anaerobic threshold (AT) in untrained male Wistar rats with different times to exhaustion (Tex ) from swimming. The first group of rats was randomly divided into six subgroups and subjected to a swimming test to exhaustion without a load or with a load of 2%-10% of body weight (BW). In the first group, we established that for untrained rats, the load of 4% BW in the swimming to exhaustion test was optimal for endurance assessment in comparison with other loads. The second group of rats went through a preliminary test with swimming to exhaustion at 4% BW and was then divided into two subgroups: long swimming time (LST, Tex > 240 min) and short swimming time (SST, Tex < 90 min). All rats of the second group performed, for 6 days, an experimental training protocol: swimming for 20 min each day with weight increasing each day. We established that the AT was 3% BW in SST rats and 5% BW in LST rats. The AT shifted to the right on the lactate curve in LST rats. Also, at the AT in the LST rats, we found significantly lower levels of blood lactate, cortisol, and NO.

Potential mechanism of transient receptor potential cation channel subfamilyV member1 combined with an ATP‑sensitive potassium channel in severe preeclampsia.

Severe preeclampsia is one of the most serious obstetric diseases. However, the pathogenesis of the disease is not fully understood. In the present study, placental artery and blood serum was collected from patients with severe preeclampsia, as well as from normal pregnant women. The results of reverse transcription-quantitative (q)PCR, western blotting, and immunohistochemical staining revealed markedly decreased transient receptor potential cation channel subfamily V member 1 (TRPV1), ATP-sensitive potassium channel (KATP) subtype Kir6.1/SUR2B and endothelial nitric oxide synthase (eNOS) expression in severe preeclampsia tissue specimens compared with those in samples from normal pregnant women. The nitrate reduction method indicated lower NO levels in the tissue specimens and serum of patients with severe preeclampsia. Moreover, hematoxylin-eosin staining showed that the endothelial cell layer in the placental artery of patients with severe preeclampsia was notably damaged. To investigate the potential role of TRPV1-KATP channels in severe preeclampsia, HUVECs were used for in vitro experiments. The samples were divided into a control group, a TRPV1 agonist group (capsaicin) and a TRPV1 inhibitor group (capsazepine). qPCR and western blotting revealed that the relative gene and protein expression levels of TRPV1, Kir6.1, SUR2B and eNOS in the control group were significantly lower than those in the capsaicin group and considerably higher than those in the capsazepine group. Based on previous studies and the results of the present study, we hypothesized that impairment of the endothelial TRPV1-KATP channels results in decreased eNOS/NO pathway activity, which may be one of the mechanisms involved in severe preeclampsia. The increase in NO generation mediated by TRPV1-KATP may be a suitable target for the management of severe preeclampsia.

Influence of natural and anthropogenic factors on the hydrogeology and hydrogeochemistry of Wadi Itwad Aquifer, Saudi Arabia: Assessment using multivariate statistics and PMWIN simulation

The quantity and quality of the aquifers have been depleted by human activities such as industrialization, the use of fertilizers, excessive pumping, and the discharge of domestic wastewater. The government of Saudi Arabia (SA) built three dams in the Wadi Itwad so that Abha city could get 15,000 m3/d of water. Ten groundwater samples have been collected from ten wells (Well 1 – Well 10) located in Wadi Itwad. The samples were analyzed for total dissolved solids (TDS), electrical conductivity (EC), pH, turbidity, temperature, chloride (Cl-), potassium (K), sulphate (SO42-), nitrate (NO3–), nitrite (NO2–), fluoride (F-), ammonia (NH4), radium (Ra)-226, 228, and 234, total uranium (TU), and total faecal coliforms to evaluate the aquifer quality and quantity and to preserve it by isolating it during dry periods. Geographic Information System (GIS)–Inverse Distance Weighting (IDW) contour maps were utilized to collect and display the aquifer's hydrogeological parameters. The southeast of the downstream area shows the highest, whereas the lowest drawdown was in the northeastern and southwest parts of the downstream area. The TDS concentration was consistently within a narrow range of 573 to 606 ppm, and the anomalies in the SO42- and NO3– concentrations were consistent with and representative of runoff from agricultural areas. The low levels of NO2–, F-, and NH4 indicated negligible pollution. The concentration of radioactive elements was below the maximum contaminant level. Different hydrogeochemical processes within the aquifer system were distinguished using multivariate statistical analyses, including correlation analysis (CA), principal component analysis (PCA), hierarchical cluster analysis (HCA), and one-way analysis of variance (ANOVA). The Processing Modflow Windows (PMWIN) groundwater modeling explains that the abstraction rate needs to be lowered during the first few days of pumping and then raised again afterwards. This could aid in decreasing withdrawals and enhancing aquifer hydrogeological properties.

1570 NOS2-derived low levels of NO drives psoriasis pathogenesis

1570 NOS2-derived low levels of NO drives psoriasis pathogenesis

Exploring nitric oxide as a crucial prognostic biomarker of coronary artery disease

PurposeThe study aimed to examine if the polymorphism of the endothelial nitric oxide synthase (eNOS) gene variable number of tandem repeats (VNTR) and the serum NO levels are associated with CAD. Materials/methodsCase-control study, 70 CAD and 30 control subjects were enrolled. The eNOS gene polymorphism was measured by polymerase chain reaction–agarose gel electrophoresis and the serum NO was assessed by using an ELISA plate and reader covering 540 nm. ResultsUncovering the area under curve (AUC) for serum NO, which was (0.6821), indicating that NO seemed to be a critical prognostic biomarker of CAD; also, glucose, serum creatinine and total bilirubin proved to be significant predictors of CAD with AUC (0.6793, 0.6717 and 0.6662) respectively. Furthermore, higher serum NO levels were associated with the eNOS (ab) genotype. Revealing the intron (a) allele was protective against CAD. Moreover, diminished levels of serum NO in CAD groups compared to controls (P < 0.05). Additionally, Multiple logistic regression analysis shows a significantly high Odds ratio associated with CAD in the Duhok population. ConclusionsThe eNOS (ab) variant seems to be a protective CAD factor for patients. Low serum NO levels are another risk factor for the advancement of CAD, suggesting their involvement in atherosclerosis. The (a) allele's protective effect is mediated through changes in eNOS promoter activity and higher NO levels.

On the transition of major pollutant and O3 production regime during Covid-19 lockdowns

Lockdowns enforced amid the pandemic facilitated the evaluation of the impact of emission reductions on air quality and the production regime of O3 under NOx reduction. Analysis of space-time variation of various pollutants (PM10, PM2.5, NOx, CO, O3 and VOC or TNMHC) through the lockdown phases at eight typical stations (Urban/Metro, Rural/high vegetation and coastal) is carried out. It reveals how the major pollutant (PM10 or PM2.5 or O3, or CO) differs from station to station as lockdowns progress depending on geography, land-use pattern and efficacy of lockdown implementation. Among the stations analyzed, Delhi (Chandnichowk), the most polluted (PM10 = 203 μgm−3; O3 = 17.4 ppbv) in pre-lockdown, experienced maximum reduction during the first phase of lockdown in PM2.5 (−47%), NO2 (−40%), CO (−37%) while O3 remained almost the same (2% reduction) to pre-lockdown levels. The least polluted Mahabaleshwar (PM10 = 45 μgm−3; O3 = 54 ppbv) witnessed relatively less reduction in PM2.5 (−2.9%), NO2 (−4.7%), CO (−49%) while O3 increased by 36% to pre-lockdown levels. In rural stations with lots of greenery, O3 is the major pollutant attributed to biogenic VOC emissions from vegetation besides lower NO levels. In other stations, PM2.5 or PM10 is the primary pollutant. At Chennai, Jabalpur, Mahabaleshwar and Goa, the deciding factor of Air Quality Index (AQI) remained unchanged, with reduced values. Particulate matter, PM10 decided AQI for three stations (dust as control component), and PM2.5 decided the same for two but within acceptable limits for stations. Improvement of AQI through control of dust would prove beneficial for Chennai and Patiala; anthropogenic emission control would work for Chandani chowk, Goa and Patiala; emission control of CO is required for Mahabaleshwar and Thiruvanathapuram. Under low VOC/NOx ratio conditions, O3 varies with the ratio, NO/NO2, with a negative (positive) slope indicating VOC-sensitive (NOx-sensitive) regime. Peak O3 isopleths as a function of NOx and VOC depicting distinct patterns suggest that O3 variation is entirely non-linear for a given NOx or VOC.

Partículas en suspensión PM10, NO2 y agudizaciones de enfermedad respiratoria crónica

ObjectivesThe new World Health Organization guidelines recommend studies with simultaneous exposure to multiple air pollutants. The main objective has been to analyze the strength of the association between different concentrations of PM10 and NO2 and the exacerbation of chronic respiratory diseases (ECRD), specifically asthma and chronic obstructive pulmonary disease. Material and methodsRetrospective cross-sectional study. The population analyzed were adults treated in an urgent and primary health care center on certain lag+1 days in 2019. Three indices have been developed (1: high levels of PM10 and NO2; 2: high level of PM10 and low level of NO2, and 3: low levels of PM10 and NO2) and a logistic regression model for each of them, with ECRD as the outcome variable, and the progressive addition of adjustment variables (sex, age, tobacco, Charlson index, season, precipitation, wind and temperature). ResultsFour hundred and sixty-one people were analyzed, 17 with ECRD. Models 1 and 2 presented very similar values in the adjusted OR (4.28 [95% CI 1.05–17]), R2 (0.88) and the area under the ROC curve (>0.72). In both of them the significance was maintained after including the adjustment variables, while model 3 only allowed the addition of precipitation. The inclusion of the Charlson index and the tobacco consumption in the 3 models implied the loss of statistical significance of the PM10/NO2 combination regarding ECRD. ConclusionsHigh levels of PM10 are related to ECRD and have a greater impact than NO2, with tobacco use and comorbidities being the main precipitants of ECRD.

Chimonanthus nitens Oliv. Leaf Granule Ameliorates DSS-Induced Acute Colitis Through Treg Cell Improvement, Oxidative Stress Reduction, and Gut Microflora Modulation.

The rising incidence of ulcerative colitis has become a new challenge for public health. Chimonanthus nitens Oliv. leaf granule (COG) is a natural medicine used for the treatment of respiratory diseases, which has excellent anti-inflammatory and antioxidant effects. However, the therapeutic effect of COG in ulcerative colitis (UC) has not been reported. Here, the experimental colitis was treated with dextran sodium sulfate (DSS) and COG. After treatment with high (30 g/kg), medium (15 g/kg), and low (7.5 g/kg) doses of COG for 11 consecutive days, the body weight, disease activity index (DAI) score, colon length, colon weight index, and the pathological score of mice were effectively improved. COG significantly reduced the levels of inflammatory cytokines in UC mice in vitro and in vivo and restored the secretion levels of IL-6 and IL-10 in the colon. Meanwhile, compared to mice with colitis, COG-treated mice showed lower levels of MDA, MPO, NO, and eNOS and higher levels of GSH-Px and MAO, which indicated that oxidative stress damage in colitic mice was alleviated by COG. Moreover, less Th17 and more Tregs were observed in the COG-treated groups. In addition, COG improved the diversity and relative abundance of gut microflora in the colon of colitic mice, and Lachnospiraceae_NK4A136_group and Lachnospiraceae_UCG-006 were obviously regulated at the genus level. In summary, COG has a protective effect on DSS-induced experimental colitis, mainly through inhibition of immune-inflammatory responses and oxidative stress and regulation of mTreg cell responses and intestinal flora composition.

Effect of cognitive rehabilitation training combined with butylphthalide soft capsules and ginkgo-leaf tablets on patients with mild Alzheimer's disease

Purpose: To study the impact of a combination of cognitive rehabilitation training, butylphthalide soft capsules and ginkgo-leaf tablets on patients with mild Alzheimer’s disease (AD).Methods: One hundred and twenty-eight (128) mild AD patients were randomly assigned to medication treatment group (MT group, n = 64) and joint training group (JT group, n = 64). Both groups were treated with butylphthalide soft capsules and ginkgo-leaf tablets, while the JT group additionally received cognitive rehabilitation training. Therapeutic effects and adverse drug reactionsin the two groups were assessed.Results: Total effectiveness was significantly higher in JT patients (84.38 %) than in MT patients (60.94 %; χ2 = 8.9320). After treatment, Mini-Mental State Exam (MMSE), Activity of Daily Living (ADL) and ADAS-cog scores in the JT group were significantly better than those in the MT group, (p &lt; 0.05). There were significantly lower plasma NO, serum VEGF and MDA levels in JT patients than in MT patients. CRP and Hcy levels were markedly lower in JT than in MT patients. The incidence of adverse reactions in both groups was comparable (p &gt; 0.05).Conclusion: Rehabilitation training in combination with butylphthalide soft capsule and ginkgo-leaf tablets produce significant therapeutic impact on mild AD patients. The combination therapy delays cognitive decline and memory loss in AD patients, improves their serological indicators, and lowers the incidence of adverse reactions.

Air Quality in Two Northern Greek Cities Revealed by Their Tropospheric NO2 Levels

In this article, we aim to show the capabilities, benefits, as well as restrictions, of three different air quality-related information sources, namely the Sentinel-5Precursor TROPOspheric Monitoring Instrument (TROPOMI) space-born observations, the Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) ground-based measurements and the LOng Term Ozone Simulation-EURopean Operational Smog (LOTOS-EUROS) chemical transport modelling system simulations. The tropospheric NO2 concentrations between 2018 and 2021 are discussed as air quality indicators for the Greek cities of Thessaloniki and Ioannina. Each dataset was analysed in an autonomous manner and, without disregarding their differences, the common air quality picture that they provide is revealed. All three systems report a clear seasonal pattern, with high NO2 levels during wintertime and lower NO2 levels during summertime, reflecting the importance of photochemistry in the abatement of this air pollutant. The spatial patterns of the NO2 load, obtained by both space-born observations and model simulations, show the undeniable variability of the NO2 load within the urban agglomerations. Furthermore, a clear diurnal variability is clearly identified by the ground-based measurements, as well as a Sunday minimum NO2 load effect, alongside the rest of the sources of air quality information. Within their individual strengths and limitations, the space-borne observations, the ground-based measurements, and the chemical transport modelling simulations demonstrate unequivocally their ability to report on the air quality situation in urban locations.

Novel Insights Into Leishmania (Viannia) braziliensis In Vitro Fitness Guided by Temperature Changes Along With Its Subtilisins and Oligopeptidase B.

Proteases are virulence factors with a recognized impact on the Leishmania spp. life cycle. This study considers a set of analyses measuring phenotypic factors of L. (V.) braziliensis clinical isolates as promastigotes growth curves, murine peritoneal macrophages infection, inflammatory mediators production, and serine proteases gene expression (subtilisin 13: S13, subtilisin 28: S28, oligopeptidase B: OPB) assessing these isolates’ fitness on in vitro conditions. Parasites had different behavior during the early growth phase from day zero to day three, and all isolates reached the stationary growth phase between days four and seven. Macrophages infection showed two tendencies, one of decreased infection rate and number of parasites per macrophage (Infection Index <1000) and another with a constant infection index (≥1400). TNF-α (≥10 pg/mL) detected in infections by 75% of isolates, IL-6 (≥80 pg/mL) by 30% of isolates and low levels of NO (≥0.01µM) in almost all infections. Gene expression showed higher values of S13 (≥2RQ) in the intracellular amastigotes of all the isolates evaluated. On the contrary, S28 expression was low (≤1RQ) in all isolates. OPB expression was different between promastigotes and intracellular amastigotes, being significantly higher (≥2RQ) in the latter form of 58% of the isolates. Predictive structural assays of S13 and OPB were performed to explore temperature influence on gene expression and the encoded proteases. Gene expression data is discussed based on in silico predictions of regulatory regions that show plasticity in the linearity index of secondary structures of S13 and OPB 3’-untranslated regions of mRNA, dependent on temperature changes. While hairpin structures suggest an active region of mRNA for both genes above 26°C, pseudoknot structure found in S13 is an indication of a particular profile of this gene at mammalian host temperatures (37°C). Furthermore, the predicted 3D structures are in accordance with the influence of these temperatures on the catalytic site stability of both enzymes, favoring their action over peptide substrates. Data gathered here suggest that L. (V.) braziliensis serine proteases can be influenced by the temperature conditions affecting parasite fitness throughout its life cycle.

Biological reference interval of nitric oxide in health and disease.

There is a need to develop reference interval of NO in health and disease. Subjects aged between 25 and 55 years were drawn from a random sample of the north Indian population, based on defined inclusion and exclusion criteria. Measurement of NO was done based on principle of greiss reaction. Reference interval of NO in healthy individual of age group 25-55 years was 21±13.3μM/L (n=350), Premenopausal women of age group 25-35 years was 12.7±4.9μM/L (n=180), Postmenopausal women of age group 40-55 years was 10.3±3.84μM/L (n=100) and healthy pregnant females of age group 25-35 years was 70.9±15.95μM/L (n=330). In pathological state group, reference interval of NO in metabolic syndrome cases of age group 25-55 years was 19.4±15.3μM/L (n=100), coronary artery disease patient of age group more than 35 years was 17.6±10.8μM/L (n=160), pregnancy induced hypertension (PIH) of age group 25-30 years was 45.7±7.2μM/L (n=330), pre-eclampsia patient of age group 25-35 years was 39.8±14.7μM/L (n=200) and diabetic individuals of age group of more than 30 years was 15.5±1.4μM/L (n=50). The reference intervals presented may be used for various research purposes. Based upon our study, reference interval for NO levels of various disease states like MetS, CAD, diabetes, PIH showed lower levels of NO compared to their respective healthy group due to shared etiopathologies with decreased NO levels.

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma.

The venom of the “armed” spider Phoneutria nigriventer comprises several potent toxins. One of the most toxic components from this venom is the neurotoxin PnTx2-6 (LD50 = ∼ 0.7 μg/mouse, 48 residues, five disulfide bridges, MW = 5,289.31 Da), which slows down the inactivation of various Na+ channels. In mice and rats, this toxin causes priapism, an involuntary and painful erection, similar to what is observed in humans bitten by P. nigriventer. While not completely elucidated, it is clear that PnTx2-6 potentiates erectile function via NO/cGMP signaling, but it has many off-target effects. Seeking to obtain a simpler and less toxic molecule able to retain the pharmacological properties of this toxin, we designed and synthesized the peptide PnPP-19 (19 residues, MW = 2,485.6 Da), representing a discontinuous epitope of PnTx2-6. This synthetic peptide also potentiates erectile function via NO/cGMP, but it does not target Na+ channels, and therefore, it displays nontoxic properties in animals even at high doses. PnPP-19 effectively potentiates erectile function not only after subcutaneous or intravenous administration but also following topical application. Surprisingly, PnPP-19 showed central and peripheral antinociceptive activity involving the opioid and cannabinoid systems, suggesting applicability in nociception. Furthermore, considering that PnPP-19 increases NO availability in the corpus cavernosum, this peptide was also tested in a model of induced intraocular hypertension, characterized by low NO levels, and it showed promising results by decreasing the intraocular pressure which prevents retinal damage. Herein, we discuss how was engineered this smaller active non-toxic peptide with promising results in the treatment of erectile dysfunction, nociception, and glaucoma from the noxious PnTx2-6, as well as the pitfalls of this ongoing journey.

Experimental investigation of urea injection strategy for close-coupled SCR aftertreatment system to meet ultra-low NO emission regulation

• The tailpipe NOx and PM emission satisfy CARB ultra-low emission regulation under FTP cycle. • The effect of temperature and space velocity on NO x conversion is investigated. • A high NO x conversion efficiency is observed on ccSCR with air-assisted urea nozzle. • A zonal control strategy for dual urea injection is adopted to reduce tailpipe NOx emission. • The supplemental urea injection strategy is effective to reduce tailpipe NOx emission. Worldwide automotive emission regulations for heavy-duty diesel engines are increasingly stringent, especially for nitrogen oxide (NO x ) and particulate matter (PM). The development of high-efficiency aftertreatment technologies and the optimization of the urea injection strategies are key factors for the diesel engines to meet the future regulations. In this paper, the effects of temperature and space velocity on close coupled selective catalyst reduction (ccSCR) and SCR are investigated firstly. The highest NO x conversion efficiency of ccSCR and main SCR is observed at 350 °C, and an increase of space velocity leads to a more significant decrease on NO x conversion efficiency of ccSCR than that of SCR. Then three phases of urea injection state for both nozzles are determined according to the catalyst inlet temperature in the Federal Test Procedure (FTP) cycle. Urea injection strategy is optimized by urea injection ratio calibration and urea injection strategy updating based on the characteristic of three phases, as well as NH 3 sensor feedback. Finally, the composite tailpipe NO x emission under FTP cycle is reduced below 0.027 g/kW·h, satisfying California air resources board (CARB) ultra-low NO x emission regulation with a penalty of slight increase in CO 2 emissions. However, adopting a high reactivity gasoline can improve the efficiency while maintaining the low level of NO x emissions.

Abstract WP16: Characterizing Cd38 Expression And Activity In The Brain Of Spontaneously Hypertensive Stroke Prone Rats

Introduction: CD38 is an ectoenzyme that is the main source of age dependent decrease in NAD + levels. Its role in cerebral small vessel disease (cSVD) is unknown. We hypothesize that CD38 is over-expressed and activated in spontaneously hypertensive stroke-prone rat (SHRSP), a model of human cSVD. Methods: 20 SHRSP and 20 age matched male Wistar Kyoto control rats (WKY) were studied. Systolic blood pressure (SBP) was measured weekly using tail-cuff plethysmography. Half of the groups were euthanized at 7 weeks of age (Wks) and the remaining rats were followed until 24 Wks. Routine histology and immunohistochemistry (IHC) were performed for nitric oxide synthase (NOS) subtypes, superoxides (DHE), NO (DAF), and NADPH. IHC was used to detect CD38 expression and co-staining determined expression on endothelial cells (eNOS), astrocytes (GFAP), microglia (Iba1), T cells (CD3), macrophages (CD68), neutrophils (MPO) and neurons (Neuon). CD38 activity was detected in the brain homogenate by using a substrate analog of NAD + with measurement of its conversion to the strongly fluorescent product (ε-ADPR). Results: Compared to WKY, SHRSP developed hypertension between (9 -12) Wks and sustained it afterwards (SBP: 19 Wks: WKY 142.5±11.8 mmHg vs SHRSP 180.3±12.8 mmHg, P&lt;0.0001). At 24 Wks, SHRSP showed histological evidence of cSVD including microbleed, enlarged perivascular spaces, and lipohyalinosis. Compared to WKY, CD38 expression was increased in SHRSP brain (7 Wks: 102.6%, P=0.011, 24 Wks: 83.2%, p=0.0077). CD38 activity was also significantly higher in SHRSP (7 Wks: 11.8%, p=0.012, 24 Wks: 20.2%, p=0.0065). We identified CD38 expression on endothelial cells, astrocytes and microglia. In comparison to WKY, SHRSP showed lower levels of NADPH (7 Wks: 22.3%, p=0.029, 24 Wks: 65.5%, p=0.0065), NO (7 Wks: 39.3% p=0.0008, 24 Wks: 36%, p=0.04), endothelial NOS (7 Wks: 57.5%, p=0.02, 24 Wks: 50.6%, p=0.01) and higher superoxide (7 Wks: 131%, p&lt;0.0001, 24 Wks: 163%, p&lt;0.0001). Conclusions: The brain of SHRSP shows evidence for elevated CD38 activity and expression with associated oxidative stress, depletion of NADPH and eNOS dysfunction compared to normotensive WKY. These results suggest the potential role of CD38 based therapeutics in future management of human cSVD.