The Effect of a Neuronal Nitric Oxide Synthase Inhibitor on Neurovascular Regulation in Humans.

BACKGROUND: Neurovascular coupling (NVC) is a key process in cerebral blood flow regulation. NVC ensures adequate brain perfusion to changes in local metabolic demands. Neuronal nitric oxide synthase (nNOS) is suspected to be involved in NVC; however, this has not been tested in humans. Our objective was to investigate the effects of nNOS inhibition on NVC in humans. METHODS: We performed a 3-visit partially randomized, double-blinded, placebo-controlled, crossover study in 12 healthy subjects. On each visit, subjects received an intravenous infusion of either S-methyl-L-thiocitrulline (a selective nNOS-inhibitor), 0.9% saline (placebo control), or phenylephrine (pressor control). The NVC assessment involved eliciting posterior circulation hyperemia through visual stimulation while measuring posterior and middle cerebral arteries blood velocity. RESULTS: nNOS inhibition blunted the rapidity of the NVC response versus pressor control, evidenced by a reduced initial rise in mean posterior cerebral artery velocity (-3.3% [-6.5, -0.01], P=0.049), and a reduced rate of increase (ie, acceleration) in posterior cerebral artery velocity (slope reduced -4.3% [-8.5, -0.1], P=0.045). The overall magnitude of posterior cerebral artery response relative to placebo control or pressor control was not affected. Changes in BP parameters were well-matched between the S-methyl-L-thiocitrulline and pressor control arms. CONCLUSIONS: Neuronal NOS plays a role in dynamic cerebral blood flow control in healthy adults, particularly the rapidity of the NVC response to visual stimulation. This work opens the way to further investigation of the role of nNOS in conditions of impaired NVC, potentially revealing a therapeutic target.

Direct cardiac versus systemic effects of inorganic nitrite on human left ventricular function.

Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 µmol/min, n = 20) or an intravenous sodium nitrite infusion (50 µg/kg/min, n = 20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction.NEW & NOTEWORTHY This is the first study to assess the direct and indirect effects of inorganic nitrite on invasive measures of left ventricular function in humans in vivo. Inorganic nitrite has a modest direct myocardial effect, improving diastolic function. Systemic administration of nitrite has larger effects related to alterations in cardiac preload and afterload. The changes induced by nitrite appear favorable for potential use in conditions characterized by LV diastolic dysfunction.

Alpha-1antitrypsin in pre-eclampsia; from a clinical perspective.

OBJECTIVE: To assess serum Alpha-1 antitrypsin (AAT) levels in women with pre-ecclampsia and correlate them with other parameters of pre-eclampsia. METHODS: A case-control study was conducted at Al-Yarmouk Teaching Hospital, Baghdad from February 2019 to February 2020. Included were 85 pregnant women with 32-34 weeks of gestation. They were divided in 2 groups: pre-eclamptic cases 40/85, and normotensive controls (45/85). PE was defined based on NICE 2018 guidelines. Patients' age and blood pressure (BP) were recorded. We evaluated mean platelet volume (MPV), platelet distribution width (PDW), serum levels of uric acid, and AAT blood samples. RESULTS: AAT levels were significantly lower among preeclamptic cases (0.26) mg/dl versus controls (0.63) mg/dl. Negative correlations were found between levels of AAT and other variables (systolic BP, diastolic BP, MPV, PDW, and serum uric acid levels) with a coefficient of correlation ( r) -0.43,-0.43,-0.25,-0.25, and- 0.26 respectively. P-value <0.05 was estimated for all. CONCLUSION: Significant lower levels of AAT in pre-eclamptic patients versus controls suggest that it contributes to pre-eclampsia development. The second finding was negative correlations of reduced AAT with the most common maternal parameters assessing pre-eclampsia severity. Taken together, these results indicate that AAT is intimately linked to the pathophysiology of PE development and progression. Further work is warranted to verify the AAT role in pre-eclampsia.

Nootkatone Mitigated Melamine-Evoked Hepatotoxicity by Featuring Oxidative Stress and Inflammation Interconnected Mechanisms: In Vivo and In Silico Approaches.

Melamine (ML) is a common environmental contaminant, commonly used in food fraud, representing a serious health hazard and jeopardizing human and animal health. Recently, nootkatone (NK), a naturally occurring sesquiterpenoid, has garnered considerable attention due to its potential therapeutic advantages. We investigated the potential mechanisms underlying the protective effects of NK against ML-induced liver injury in rats. Five groups were utilized: control, ML, NK10, ML-NK5, and ML-NK10. ML induced substantial hepatotoxicity, including considerable alterations in biochemical parameters and histology. The oxidative distress triggered by ML increased the generation of malondialdehyde (MDA) and nitric oxide (NO) and decreased levels of reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. In addition, decreased expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased nuclear factor kappa beta (NF-κB) expression levels were observed in hepatocytes, which indicated the occurrence of inflammatory changes following ML exposure. These alterations were alleviated by NK supplementation in a dose-dependent manner. The data revealed that the favorable effects of NK were attributed, at least in part, to its antioxidant and anti-inflammatory properties. Moreover, our results were supported by molecular docking studies that revealed a good fit and interactions between NK and antioxidant enzymes. Thus, the current study demonstrated that NK is a potential new food additive for the prevention or treatment of ML-induced toxicity.

Macro, Micro, and Nano-Inspired Bioactive Polymeric Biomaterials in Therapeutic, and Regenerative Orofacial Applications.

Introducing dental polymers has accelerated biotechnological research, advancing tissue engineering, biomaterials development, and drug delivery. Polymers have been utilized effectively in dentistry to build dentures and orthodontic equipment and are key components in the composition of numerous restorative materials. Furthermore, dental polymers have the potential to be employed for medication administration and tissue regeneration. To analyze the influence of polymer-based investigations on practical medical trials, it is required to evaluate the research undertaken in this sector. The present review aims to gather evidence on polymer applications in dental, oral, and maxillofacial reconstruction.

ß-Adrenergic receptor signaling increases NAADP and cADPR levels in the heart.

Evidence suggests that ß-Adrenergic receptor signaling increases heart rate and force through not just cyclic AMP but also the Ca(2+)-releasing second messengers NAADP (nicotinic acid adenine dinucleotide phosphate) and cADPR (cyclic ADP-ribose). Nevertheless, proof of the physiological relevance of these messengers requires direct measurements of their levels in response to receptor stimulation. Here we report that in intact Langendorff-perfused hearts ß-adrenergic stimulation increased both messengers, with NAADP being transient and cADPR being sustained. Both NAADP and cADPR have physiological and therefore pathological relevance by providing alternative drug targets in the ß-adrenergic receptor signaling pathway.

Evaluation of Bone Mineral Density, Serum Osteocalcin, and Osteopontin Levels in Postmenopausal Women with Type 2 Diabetes Mellitus, with/without Osteoporosis.

OBJECTIVE: Osteoporosis (OP) is a worldwide ailment; we aim to establish new biomarkers in diagnosis by determining the levels of serum osteocalcin and osteopontin along with bone mineral density (BMD) and lumbar T-score, in postmenopausal women with type 2 diabetes mellitus (T2DM) with or without OP. METHODS: This observational study included 160 postmenopausal women who were an attendee at outpatient clinics in Al-Hussein Hospital, Thi-Qar province; subdivided into 3 groups based on their T-score testing: Group I (n = 40) comprised postmenopausal women without T2DM as controls, Group II (n = 60) comprised postmenopausal women with T2DM but without OP, and Group III (n = 60) comprised postmenopausal women with T2DM with OP. The dual-energy X-ray absorptiometry was used to measure the BMD (total body, lumbar spine, and femoral) and T-score for lumbar spine and femoral. Glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), osteocalcin, and osteopontin levels were assessed in all three groups. RESULTS: Compared with controls, Group III demonstrated significantly lower BMD (total body, lumbar spine, and femoral), T-score for lumbar spine and femoral, serum osteocalcin, and osteopontin levels than Group II and Group I (P < 0.001). FBG and HbA1c levels were significantly higher in Group III than in Groups I and II (P < 0.001). A negative correlation was proved between HbA1c levels with BMD, osteocalcin levels, and osteopontin levels in the three groups. CONCLUSIONS: Iraqi postmenopausal women with T2DM had a significantly lower bone mineral density, serum osteocalcin, and osteopontin levels. These results may serve as adjuvants in screening for OP, particularly among diabetic patients.

Recent advances in biosensor devices for HER-2 cancer biomarker detection.

The human epidermal growth factor receptor 2 (HER-2) protein is a member of the epidermal growth factor receptor (EGFR or ErbB) family and is a transmembrane tyrosine kinase receptor. HER-2 is highly regulated in ovarian, lung, gastric, oral, and breast cancers. The low specificity, complexity, expensiveness and the lack of sensitivity are essential restrictions in traditional diagnosis methods such as FISH, immunohistochemistry and PCR and these disadvantages led to the need for more studies on alternative methods. Biosensor technology has greatly affected the quality of human life owing to its features including, sensitivity, specificity, and rapid diagnosis and monitoring of different patient diseases. In this review article, we examine various biosensors, considering that they have been categorized based on the transducers used including piezoelectric biosensors, optical sensors such as fluorescence and surface plasmon resonance, and electrochemical types for the diagnosis of HER-2 and the effectiveness of some drugs against that. Attention to developing some types of biosensor devices such as colorimetric biosensors for HER-2 detection can be an important point in future studies.

Catalytic filtration: efficient C-C cross-coupling using Pd(II)-salen complex-embedded cellulose filter paper as a portable catalyst.

A new approach has been developed for environmentally friendly C-C cross-coupling reactions using bi-functional Pd(ii)-salen complex-embedded cellulose filter paper (FP@Si-PdII-Salen-[IM]OH). A Pd(ii)-salen complex bearing imidazolium [OH]-moieties was covalently embedded into a plain filter paper, then used as an efficient portable catalyst for the Heck, Suzuki, and Sonogashira cross-coupling reactions under environmentally friendly conditions via the filtration method. The catalytic filter paper properties were studied by EDX, XPS, TGA, ATR, XRD, and FESEM analyses. The reactions were catalyzed during reactants' filtration over the catalytic filter paper. The modified filter paper was set up over a funnel and the reactants were passed through the catalytic filter paper several times. The effect of reaction parameters including loading of Pd(ii)-salen complex, temperature, solvent, and contact time were carefully studied and also the optimal model of conditions was presented by the design expert software. High to excellent yields were obtained for all C-C coupling types with 5 to 8 filtration times. Under optimal conditions, all coupling reactions showed high selectivity and efficiency. Another advantage of the modified filter paper was its stability and reusability for several times with preservation of catalytic activity and swellability.

Lower Serum Irisin Levels Are Associated with Increased Osteoporosis and Oxidative Stress in Postmenopausal.

BACKGROUND: Irisin as an exercise-induced myokine was proposed to improve bone health. This study investigated the role of serum irisin (s-irisin) in patients with osteoporosis (OP) through correlating to most biological bone markers and oxidative stress. METHODS: A cross-sectional study recruited an eligible 175 postmenopausal women at Al-Hussien Teaching Hospital, Iraq. They were scanned by DEXA and stratified into two groups based on T-score; the first 95 patients as control group (GI) with -1 ≤ T-score and the second 80 patients as cases group (GII) with T-score ≤ -2.5. Demographic criteria were age, bone mineral density (BMD, g/cm2) and T-score. Serum irisin, total serum calcium (s-calcium), serum inorganic phosphate (s-phosphate), serum alkaline phosphatase (s-ALP), serum 25 [OH] vitamin D, the serum parathyroid hormone (s-PTH), serum Carboxy terminal collagen crosslinks (CTx), serum procollagen type I C-termidnal peptide (s-PICP), serum malondialdehyde (s-MDA) and serum superoxide dismutase (s-SOD) were collected from blood samples. RESULTS: Serum irisin were 31.84 ± 2.65 vs. 20.88 ± 2.71 ng/mL for control and trial groups, respectively. Lower levels of BMD, T-score, 25 [OH] vitamin D, and s-irisin along with a higher serum levels of PTH, CTx, PICP, MDA and SOD were observed in patients with osteoporosis. All parameters were statistically meaningful upon correlation (p< 0.0001), except age and s-calcium (p= 0.0088 and p= 0.187, respectively). CONCLUSION: The results showed that, a significantly lower serum irisin levels among osteoporosis women, was intimately correlated to most bone turnover markers and it can be considered as encouraging results for clinical application in prediction and treatment of osteoporosis.

The Value of Serum Adiponectin in Osteoporotic Women: Does Weight Have an Effect?

Osteoporosis (OP) has been observed to have a deleterious effect on postmenopausal women's life quality by increasing the risk of fragility fractures. The current research was adopted to verify the role of serum adiponectin, a cytokine released by adipose tissue, as a marker for OP across different body mass index groups, for a better understanding of fatty tissue role in OP. A case-control study recruited 210 eligible postmenopausal women and subgrouped into three groups based on their DEXA scan results: osteoporotic group, osteopenia group, and healthy controls; each includes 70 patients. Three datasets were collected: anthropometric, age, menopause duration, weight, height, body mass index (BMI), waist circumference, and fat percentage. Radiological examination estimated the bone mineral density (BMD) for the femoral neck and lumbar spines with their respective T-score. From blood, we measured alkaline phosphatase and calcium by a spectrophotometer and serum adiponectin, phosphate, CTX, and PICP by ELIZA. Total BMD, T-score, serum phosphate, and PICP were significantly higher among healthy controls. Serum adiponectin, CTX, and ALP scored higher levels among OP cases. A strong inverse relationship was proved between serum adiponectin and T-score in osteoporotic and osteopenia groups (-0.427, -0.301). A strong negative relationship was found between serum adiponectin and total BMD in healthy controls (-0.204). All correlations were statistically significant, P value <0.001. Serum adiponectin can be a valuable marker for reduced bone mineral density among the general populace, irrespective of the body mass index. Further research is warranted to explore therapeutic and preventive applications for this adipocytokine.

Effects of Inhibition of Nitric Oxide Synthase on Muscular Arteries During Exercise: Nitric Oxide Does Not Contribute to Vasodilation During Exercise or in Recovery.

Background Basal release of nitric oxide (NO) from the vascular endothelium regulates the tone of muscular arteries and resistance vasculature. Effects of NO on muscular arteries could be particularly important during exercise when shear stress may stimulate increased NO synthesis. Methods and Results We investigated acute effects of NO synthase inhibition on exercise hemodynamics using NG-monomethyl-l-arginine (l-NMMA), a nonselective NO synthase -inhibitor. Healthy volunteers (n=10, 5 female, 19-33 years) participated in a 2-phase randomized crossover study, receiving l-NMMA (6 mg/kg, iv over 5 minutes) or placebo before bicycle exercise (25-150 W for 12 minutes). Blood pressure, cardiac output (measured by dilution of soluble and inert tracers) and femoral artery diameter were measured before, during, and after exercise. At rest, l-NMMA reduced heart rate (by 16.2±4.3 bpm relative to placebo, P<0.01), increased peripheral vascular resistance (by 7.0±1.4 mmHg per L/min, P<0.001), mean arterial blood pressure (by 8.9±3.5 mmHg, P<0.05), and blunted an increase in femoral artery diameter that occurred immediately before exercise (change in diameter: 0.14±0.04 versus 0.32±0.06 mm after l-NMMA and placebo, P<0.01). During/after exercise l-NMMA had no significant effect on peripheral resistance, cardiac output, or on femoral artery diameter. Conclusions These results suggest that NO plays little role in modulating muscular artery function during exercise but that it may mediate changes in muscular artery tone immediately before exercise.