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S-guanylation of human serum albumin is a unique posttranslational modification and results in a novel class of antibacterial agents.

8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a nitric oxide metabolite and an important second messenger. 8-Nitro-cGMP reacts with sulfhydryl groups forming a novel posttranslational modification, namely, S-guanylation. In this work, we found, by using a quantitative competition enzyme-linked immunosorbent assay procedure, that S-guanylated human serum albumin (S-cGMP-HSA) is a component of normal plasma, and that hemodialysis patients decrease its concentration, on an average, from 68 to 34 nM. End-stage renal disease is often accompanied by septicemia, and we found that S-cG

Antidepressant-like and neuroprotective effects of Aloysia gratissima: investigation of involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloysia gratissima (Gill. et Hook) Tronc. (Verbenaceae) is used traditionally for the treatment of headache, bronchitis, and nervous systems disorders including depression. AIM OF THE STUDY: To investigate the antidepressant-like and neuroprotective effects of Aloysia gratissima aqueous extract (AE) and the involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. MATERIALS AND METHODS: The antidepressant-like effect of AE was evaluated through behavioral despair in forced swimming test (FST) and tail suspension test (TST). Swi

Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.

Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and select

Membrane potential shifts caused by diffusible guidance signals direct growth-cone turning.

Plasma membrane potentials gate the ion channel conductance that controls external signal-induced neuronal functions. We found that diffusible guidance molecules caused membrane potential shifts that resulted in repulsion or attraction of Xenopus laevis spinal neuron growth cones. The repellents Sema3A and Slit2 caused hyperpolarization, and the attractants netrin-1 and BDNF caused depolarization. Clamping the growth-cone potential at the resting state prevented Sema3A-induced repulsion; depolarizing potentials converted the repulsion to attraction, whereas hyperpolarizing potentials had no ef

Reciprocal regulation of cGMP-mediated vasorelaxation by soluble and particulate guanylate cyclases.

Nitric oxide (NO) and atrial natriuretic peptides (ANP) activate soluble (sGC) and particulate guanylate cyclase (pGC), respectively, and play important roles in the maintenance of cardiovascular homeostasis. However, little is known about potential interactions between these two cGMP-generating pathways. Here we demonstrate that sGC and pGC cooperatively regulate cGMP-mediated relaxation in human and murine vascular tissue. In human vessels, the potency of spermine-NONOate (SPER-NO) and ANP was increased after inhibition of endogenous NO synthesis and decreased by prior exposure to glyceryl t

Guanylyl cyclase stimulatory coupling to K(Ca) channels.

We coexpressed the human large-conductance, calcium-activated K (K(Ca)) channel (alpha- and beta-subunits) and rat atrial natriuretic peptide (ANP) receptor genes in Xenopus oocytes to examine the mechanism of guanylyl cyclase stimulatory coupling to the channel. Exposure of oocytes to ANP stimulated whole cell K(Ca) currents by 21 +/- 3% (at 60 mV), without altering current kinetics. Similarly, spermine NONOate, a nitric oxide donor, increased K(Ca) currents (20 +/- 4% at 60 mV) in oocytes expressing the channel subunits alone. Stimulation of K(Ca) currents by ANP was inhibited in a concentra

Exploiting autophagy-targeting natural compounds for potential antimicrobial actions.

Natural products are biologically active compounds used for therapeutic interventions for various diseases, particularly infections. Autopha … endent protein kinase kinase 2; CBD: cannabidiol; CF: cystic fibrosis; CGA: chlorogenic acid; CGAS: cyclic GMP-AMP synthase; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CLP: cecal ligation and puncture; CLR: clarithromycin; CMA: chaperone-mediated autophagy; CoV: coronavirus; DHT: dihydrotanshinone I; EGCG: epigallocatechin-3- …

Role of estrogen receptor β selective agonist in ameliorating portal hypertension in rats with CCl4-induced liver cirrhosis.

AIM: To investigate the role of diarylpropionitrile (DPN), a selective agonist of estrogen receptor β (ERβ), in liver cirrhosis with portal hypertension (PHT) and isolated hepatic stellate cells (HSCs). METHODS: Female Sprague-Dawley rats were ovariectomized (OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin (HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vi

Atrial natriuretic peptide-mediated inhibition of microcirculatory endothelial Ca2+ and permeability response to histamine involves cGMP-dependent protein kinase I and TRPC6 channels.

OBJECTIVE: Histamine increases microvascular endothelial leakage by activation of complex calcium-dependent and -independent signaling pathways. Atrial natriuretic peptide (ANP) via its cGMP-forming guanylyl cyclase-A (GC-A) receptor counteracts this response. Here, we characterized the molecular mechanisms underlying this interaction, especially the role of cGMP-dependent protein kinase I (cGKI). APPROACH AND RESULTS: We combined intravital microscopy studies of the mouse cremaster microcirculation with experiments in cultured microvascular human dermal endothelial cells. In wild-type mice,

Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells.

We previously reported that C-type natriuretic peptide (CNP) stimulates endochondral ossification and corrects the reduction in body length of achondroplasia model mouse with constitutive active fibroblast growth factor receptor 3 (FGFR-3). In order to examine the interaction between CNP and FGFR-3, we studied intracellular signaling by using ATDC5 cells, a mouse chondrogenic cell line, and found that FGF2 and FGF18 markedly reduced CNP-dependent intracellular cGMP production, and that these effects were attenuated by MAPK inhibitors. Western blot analysis demonstrated that the level of GC-B,

On the regulation of NMDA receptors by nitric oxide.

Nitric oxide (NO) is generated in central synapses on activation of N-methyl-D-aspartate (NMDA) receptors and exerts physiological effects by changing cGMP levels. NO has frequently also been claimed to engage a different mechanism, namely the covalent modification of thiol residues (S-nitrosation), and thereby exert a negative feedback on NMDA receptors. Tests of this hypothesis were conducted by recording NMDA receptor-mediated synaptic potentials in the CA1 area of rat hippocampal slices. Manipulations designed to increase or decrease endogenous NO levels had no effect. Addition of exogenou

Hydrogen sulfide: a novel gaseous signaling molecule and intracellular Ca2+ regulator in rat parotid acinar cells.

In addition to nitric oxide (NO), hydrogen sulfide (H2S) is recognized as a crucial gaseous messenger that exerts many biological actions in various tissues. An attempt was made to assess the roles and underlying mechanisms of both gases in isolated rat parotid acinar cells. Ductal cells and some acinar cells were found to express NO and H2S synthases. Cevimeline, a muscarinic receptor agonist upregulated endothelial NO synthase in parotid tissue. NO and H2S donors increased the intracellular Ca(2+) concentration ([Ca(2+)]i). This was not affected by inhibitors of phospholipase C and inositol

Pathological implications of iNOS expression in central white matter: an ex vivo study of optic nerves from rats with experimental allergic encephalomyelitis.

Excessive nitric oxide (NO) production from the inducible isoform of nitric oxide synthase (iNOS) has been invoked as a causative factor in many neurodegenerative disorders, including multiple sclerosis. This hypothesis has been supported by in vitro studies showing that glial iNOS expression results in toxic NO concentrations (near 1 microm). To investigate the relevance of such findings, experiments were carried out ex vivo on optic nerves from rats with exacerbated experimental allergic encephalomyelitis, a model of multiple sclerosis. The nerves displayed characteristic immunopathology and

Inducible nitric oxide synthase (iNOS) expression upregulates p21 and inhibits vascular smooth muscle cell proliferation through p42/44 mitogen-activated protein kinase activation and independent of p53 and cyclic guanosine monophosphate.

OBJECTIVE: Overexpression of the inducible nitric oxide synthase (iNOS) gene inhibits neointimal hyperplasia after arterial injury. The purpose of this study was to examine the mechanism by which nitric oxide (NO) inhibits vascular smooth muscle cell (VSMC) proliferation, specifically focusing on signaling pathways known to be activated by NO, including cyclic guanosine monophosphate (cGMP), p53, and p42/44 mitogen-activated protein kinase (MAPK). METHODS AND RESULTS: VSMCs that were subjected to iNOS gene transfer demonstrated a reduction in proliferation (80%) that was associated with a mar

Renal cortical regulation of COX-1 and functionally related products in early renovascular hypertension (rat).

Renal volume regulation is modulated by the action of cyclooxygenases (COX) and the resulting generation of prostanoids. Epithelial expression of COX isoforms in the cortex directs COX-1 to the distal convolutions and cortical collecting duct, and COX-2 to the thick ascending limb. Partly colocalized are prostaglandin E synthase (PGES), the downstream enzyme for renal prostaglandin E(2) (PGE(2)) generation, and the EP receptors type 1 and 3. COX-1 and related components were studied in two kidney-one clip (2K1C) Goldblatt hypertensive rats with combined chronic ANG II or bradykinin B(2) recept

Chapter 29: historical aspects of the major neurological vitamin deficiency disorders: overview and fat-soluble vitamin A.

The vitamine doctrine: Although diseases resulting from vitamin deficiencies have been known for millennia, such disorders were generally at … tion of retinal interacts with transducin, a G-protein, to activate phosphodiesterases that control cyclic GMP levels, which in turn modulate the release of neurotransmitter from the rod cell. Public health: Although the availability of vitamin A through food fortification and medicinal supplements virtually eliminated ocular vitamin A deficiency from develo …

Nitric oxide induces pathological synapse loss by a protein kinase G-, Rho kinase-dependent mechanism preceded by myosin light chain phosphorylation.

The molecular signaling that underpins synapse loss in neuropathological conditions remains unknown. Concomitant upregulation of the neuronal nitric oxide (NO) synthase (nNOS) in neurodegenerative processes places NO at the center of attention. We found that de novo nNOS expression was sufficient to induce synapse loss from motoneurons at adult and neonatal stages. In brainstem slices obtained from neonatal animals, this effect required prolonged activation of the soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway and RhoA/Rho kinase (ROCK) signaling. Synapse elimination involved pa

Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses.

The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVbetagal, expression of the beta-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVbetagal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVbetagal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were

Pharmacological characterization of the relaxant effect induced by adrenomedullin in rat cavernosal smooth muscle.

The aim of the present study was to determine the mechanisms underlying the relaxant effect of adrenomedullin (AM) in rat cavernosal smooth muscle (CSM) and the expression of AM system components in this tissue. Functional assays using standard muscle bath procedures were performed in CSM isolated from male Wistar rats. Protein and mRNA levels of pre-pro-AM, calcitonin receptor-like receptor (CRLR), and Subtypes 1, 2 and 3 of the receptor activity-modifying protein (RAMP) family were assessed by Western immunoblotting and quantitative real-time polymerase chain reaction, respectively. Nitrate

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic breast cancers, and bladder squamous carcinoma. Moreover, sildenafil has been reported to increase the sensitivity of

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… Cyclic GMP phosphodiesterase-5: Target of sildenafil. J. Biol. Chem. 1999;274:13729–13732. doi: 10.1074/jbc.274.20.13729. 9. Corbin J.D., Turko I.V., Beasley A., Francis S.H. … Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatr. Res. 1998;43:163–168. doi: 10.1203/00006450-199802000-00002. 38. Bhogal S., Khraisha O., Al Madani M., Treece J., Baumrucker S.J., Paul T.K. …