Downstream mechanisms of nitric oxide-mediated skeletal muscle glucose uptake during contraction.

In oher blogs, I discuss this pathway alot in reference to a number of conditions in environmental illness. In addition, I also mention how specific toxicants may "knock-out" this pathway and therefore provides clues into understanding chemical sensitivity and certain exposures. Unfortunately, it also provides evidence that some therapies that are advocated and out there in the mainstream may be counterproductive depending on the symptoms experienced. Of course, this is up to therapy doctors to determine.

"NOS-derived oxidants regulate skeletal muscle glucose uptake during ex vivo contractions via a cGMP/PKG-, AMPK-, and p38 MAPK-independent pathway. In addition, it appears that NO and ROS may regulate skeletal muscle glucose uptake during contraction through a similar pathway."



Merry, T. L., Lynch, G. S. & McConell, G. K. Downstream mechanisms of nitric oxide-mediated skeletal muscle glucose uptake during contraction. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 299, R1656-R1665 (2010). URL http://dx.doi.org/10.1152/ajpregu.00433.2010.

Elevated Levels of Ammonia Impair the NO/cGMP Through Alterations of Cellular Transporters~!

In other blogs, I have suggested that alterations in the NO/cGMP pathway by environmental factors may influence environmental disease including CFS and MCS. Several recent studies have suggested a relationship between the NO/cGMP pathway and the activation of the Nrf2. Because the Nrf2 has a neuroprotective role on astrocytes and neurons, the failure of this pathway could contribute to neurological damage commonly associated with aging as well as, other neurological disorders. In this most recent study, the author provides more evidence that in cases of hyperammonemia, the No/cGMP pathway activity is decreased and therefore, may provide some explanation for damage resulting from high ammonia levels.

"reduced delivery of Arg due to enhanced y(+)LAT2-mediated exchange of extracellular Gln for intracellular Arg may contribute to the decrease of NO/cGMP pathway activity evoked in the brain by HA."

Zielińska, M., Ruszkiewicz, J., Hilgier, W., Fręśko, I., and Albrecht, J. (2010). Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y(+)LAT2 in rat cerebral cortex: implications for the nitric oxide/cGMP pathway. Neurochemistry international. http://www.citeulike.org/user/HEIRS/article/8341074
Sidoryk-Wegrzynowicz, M., Wegrzynowicz, M., Lee, E., Bowman, A., and Aschner, M. (2010). Role of Astrocytes in Brain Function and Disease. Toxicologic pathology.  http://www.citeulike.org/user/HEIRS/article/8341171

Ammonia Upregulates Membrane Channel Associated with Autoimmune Conditions in Astrocytes~!

"Ammonium chloride induced upregulation of aquaporin-4 in astrocytes is regulated by the p38 mitogen-activated protein kinase pathway. Inhibiting p38 activation prevented ammonium chloride induced aquaporin-4 protein upregulation." It has been suggested that aquaporins are responsible for autoimmune-type conditions including MS and past studies show it upregulates the inflammatory cytokine that initiates the inflammatory cascade that increases oxidative stress via NO.

CiteULike: Ammonia induces upregulation of aquaporin-4 in neocortical astrocytes of rats through the p38 mitogen-activated protein kinase pathway.:


Reference: (2005). Aquaporin-4, water channel protein implicated in a disorder similar to multiple sclerosis. http://www.citeulike.org/user/HEIRS/article/7859740
Sinke, A. P., Jayakumar, A. R., Panickar, K. S., Moriyama, M., Reddy, P. V., and Norenberg, M. D. (2008). Nfkappab in the mechanism of ammonia-induced astrocyte swelling in culture. Journal of neurochemistry, 106(6):2302-2311.

Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation

Seems to me that the findings from this author are pretty important....:)

"up-regulation of HO-1 in astrocytes is associated with down-regulation of iNOS expression and thereby NO production, an effect that involves the p38 MAPK signaling pathway, which suggests that this glial cell response could play an important protective role against oxidative stress in the brain."

"Sheng, W., Hu, S., Nettles, A., Lokensgard, J., Vercellotti, G., and Rock, R. (2010). Hemin inhibits no production by il-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 mapk activation. Journal of Neuroinflammation, 7(1):51+."

Read more: CiteULike: Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation:

Cell signaling mediated by nitrated cyclic guanine nucleotide.

"8-Nitro-cGMP activated the Nrf2 signaling pathway by triggering dissociation of Keap1, via S-guanylation of its highly nucleophilic cysteine sulfhydryls. We also determined that S-guanylation of Keap1 was involved in cytoprotective actions of NO and 8-nitro-cGMP by inducing oxidative stress response genes such as heme oxygenase-1"


Read more: CiteULike: Cell signaling mediated by nitrated cyclic guanine nucleotide.:

Essential role of ER-alpha-dependent NO production... [Am J Physiol Heart Circ Physiol. 2010] - PubMed result

Well....well!  More evidence of sexual dimorphism.....????


Essential role of ER-alpha-dependent NO production... [Am J Physiol Heart Circ Physiol. 2010] - PubMed result: "These data thus suggest that RESV inhibits vascular proliferative responses after injury, predominately through an ER-alpha-dependent increase in NO production."

Endotoxin and Loss of Tolerance via Reduced HO-1: Potential Mechanism in CFS and MCS?

It has been suggested that chemical sensitivity and possibly other environmental illness conditions can be the result of a "loss of tolerance".  Notably, this "loss of tolerance" may be the result of altered signaling of the immune response and contrbuting factors may include the presence of endotoxin which can 1) activate inflammatory responses, 2) reduce the threshold of reactions to allergens and 3) alter gene expression from ROS and alterations in methylation. In addition, endotoxin through activtion of GSK3b provides a mechanism to "deactivate" the antioxidant system, Nrf2. High fat diets and hyperglycemia may also promote the translocation of bacteria in the respiratory and intestinal tract. This may further increase inflammation and promote neuroinflammation in the brain as a consequence of cytokine activity in the intestinal tract and liver. At some point, the break down of the blood brain barrier may increase the likelihood of brain inflammation and changes in behavior and neurotransmission.

A recent study provides support for the hypothesis of "loss of tolerance" in environmental illness because of the role of Nrf2 as a master regulator of detoxification.  Heme oxygease is an antioxidant that is regulated by Nrf2. Naidu explains that past research has demonstrated that HO-1 deficient animals are highly susceptable to toxicity from endotoxin. Further " the potential significance of HO-1 in the adaptive immune system has been implied by a recent report, in which genetic deficiency of HO-1 decreased the suppressive activity of regulatory T cells (8)." This loss of supression could suggest a possible explanation of some symptoms related to environmental illness, especially chemical sensitivity and to some extent chronic fatigue syndrome.  There is debate on the benefits and potential harmful effects of  exercise on the latter and there are now a number of reports that demonstrate that exercise elevates HO-1 expression. On the other hand, it also can lead to an increase of translocation of bacteria that are alway present in the gut, even though the balance of gut may be different at one point vs another. In any event, the effect of exercise on bacteria translocation and HO-1 levels offer an explanation why some patients improve with exercise while others do not. As Naidu explains, there may be multiple pathways for the expession of HO-1 and may be species specific. Interestingly, he does point out that inhibition of the P38 pathway contributes to HO-1 expression at least in this study and this expression occurs via regulation by Nrf2 and reactive species are involved with this activation. This supports other research that blockade of the P38 pathway increases the expression of NO by endotoxin.


Naidu, S., Vijayan, V., Santoso, S., Kietzmann, T., and Immenschuh, S. (2009). Inhibition and genetic deficiency of p38 mapk up-rregulates heme oxygenase-1 gene expression via nrf2. Journal of Immunology, 182:7048-7057.  http://www.citeulike.org/user/HEIRS/article/7586285

Endotoxin-induced Enzyme Causes Depressive Symtoms Before Cytokine/NO Production~!

"IDO by direct application of LPS was preceded by synthesis and secretion of TNFalpha and IL-6 protein and activation of iNOS while IFNgamma expression was undetectable."

CiteULike: Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures

CiteULike: Lack of Guanylate Cyclase C results in increased mortality in mice following liver injury

CiteULike: Lack of Guanylate Cyclase C results in increased mortality in mice following liver injury: "GC-C promotes hepatocyte survival in vivo and is required for effective recovery from acute toxic injury to the liver in a strain-specific manner."

Inactivation of Foxo3a and Subsequent Downregulation of PGC-1alpha Mediate Nitric Oxide-Induced Endothelial Cell Migration.

Background: FOXO3a is a protein that is an important regulator of oxidative stress by modulating antioxidants like catalase, influences aging, is a tumor repressor, reduced in Nrf2 animals and may contribute to fertility problems. It is found in higher amounts in centenarians, meaning those that live to a hundred years or more. Its activity can be effected by methylation and acetylation. (Wipedia-FOXO3a)

"Borniquel, S., García-Quintáns, N., Valle, I., Olmos, Y., Wild, B., Martínez-Granero, F., Soria, E., Lamas, S., and Monsalve, M. (2010). Inactivation of foxo3a and subsequent downregulation of pgc-1alpha mediate nitric oxide-induced endothelial cell migration. Molecular and cellular biology, 30(16):4035-4044."

CiteULike: Inactivation of Foxo3a and Subsequent Downregulation of PGC-1alpha Mediate Nitric Oxide-Induced Endothelial Cell Migration.:

Release of Prostaglandin E2 and Nitric Oxide from Spinal Microglia Is Dependent on Activation of p38 Mitogen-Activated Protein Kinase.

TLR4: receptors that recognize liposaccharides on gram (-) bacteria that once activated trigger a number of different immune events.

"Our findings suggest that (a) activation of spinal microglia via TLR4 but not NK1 receptors produces PGE(2) and NO release from these cells; (b) the evoked PGE(2) release is generated by both COX-1 and COX-2, and (c) the COX-PGE(2) pathway is regulated by p38 and NOS2."

CiteULike: Release of Prostaglandin E2 and Nitric Oxide from Spinal Microglia Is Dependent on Activation of p38 Mitogen-Activated Protein Kinase.:

Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.

"These results suggest that, by recruiting cyclic GMP and PKG, nNOS-derived nitric oxide plays a novel and essential role in RAR signaling leading to ERK-dependent BDNF up-regulation in midbrain dopaminergic neurons."

Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.:

HO/CO and NO Regulate Oxytocin - Anxiety and Autism Implications?

Considering the relationship of oxytocin to behaviors such as fear, aggression and attachment, this study may have significant implications for PTSD as well as social problems such as violence and neglect. Also, it presents a question of whether a decline in the antioxidant system may also positively or negatively have an influence because it regulates HO-1.

Blockade of HO inhibited both basal and osmotically stimulated OT release, and induced a marked increase in NOS activity. These results indicate the involvement of CO in the regulation of NOS activity. The present data demonstrate that hypothalamic OT release induced by osmotic stimuli is modulated, at least in part, by interactions between NO and CO.

CiteULike: Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro.: "Gomes, D. A. A., Giusti-Paiva, A., Ventura, R. R. R., Elias, L. L. K. L., Cunha, F. Q. Q., and Antunes-Rodrigues, J. (2010). Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro. Bioscience reports, 30(5):351-357."

Critical role of NO signaling in GMP in the Nrf2 antioxidant adaptive response.

This is the first to show a substantial corroboration of the biological significance of cellular 8-nitro-cGMP formation and potential roles of 8-nitro-cGMP in the Nrf2-dependent antioxidant response.

CiteULike: The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response.: "Fujii, S., Sawa, T., Ihara, H., Tong, K. I., Ida, T., Okamoto, T., Ahtesham, A. K. K., Ishima, Y., Motohashi, H., Yamamoto, M., and Akaike, T. (2010). The critical role of nitric oxide signaling, via protein s-guanylation and nitrated cyclic gmp, in the antioxidant adaptive response. The Journal of biological chemistry."

Renal protection by a soy diet associated with restoration of NO generation.

"renal protective effect of soy protein appears to be mediated by improvement of NO generation and pointed out to caveolin-1 overexpression as a potential pathophysiological mechanism in renal disease"
CiteULike: Renal protection by a soy diet in obese Zucker rats is associated with restoration of nitric oxide generation.:

NO/cGMP Involved in Toluene Induced Hyperactivity

NO/cGMP Involved in Toluene Induced Hyperactivity

Suppression of Inflammatory Mediators by Cruciferous Vegetable-Derived Indole-3-Carbinol and Phenylethyl Isothiocyanate in Lipopolysaccharide-Activated Macrophages

I3C and PEITC both found in leafy green vegetables possess antiinflammatory effects by inhibiting the productions of NO, TNF-, and IL-10 in LPS-stimulated macrophages. NO’s inhibitory effect on I3C, in addition to decreasing the expression of iNOS, may at least partly be through interfering with iNOS enzyme activity as well as direct NO clearance activity, whereas PEITC may act through its direct NO clearance activity but not interfere with iNOS enzyme activity.

CiteULike: Suppression of Inflammatory Mediators by Cruciferous Vegetable-Derived Indole-3-Carbinol and Phenylethyl Isothiocyanate in Lipopolysaccharide-Activated Macrophages: "Tsai, J.-T., Liu, H.-C., and Chen, Y.-H. (2010). Suppression of inflammatory mediators by cruciferous vegetable-derived indole-3-carbinol and phenylethyl isothiocyanate in lipopolysaccharide-activated macrophages. Mediators of Inflammation."

HO-2 and Nitric Oxide Synthase Immunoreactivity of Bovine Olfactory Receptor Neurons and a Comparison with the Distribution of NADPH-diaphorase Staining

The coincident localization of the moderate NADPH-d activity and heme oxygenase-2 immunoreactivity in receptor cell perikarya suggest a functional association between NADPH-cytochrome P450 reductase and heme oxygenase-2. In contrast, dendritic localization of NADPH-d activity is topically and possibly functionally related to the presence of the inducible isoform of NOS. The results suggest that both CO and NO may be generated in bovine receptor neurons and thus involved in odorant stimulation. Based on immunocytochemical localization of synthesizing enzymes, NO might be regarded as a direct regulator of transduction related processes while CO might act as a modulator of the initial signal.

Heme Oxygenase-2 and Nitric Oxide Synthase Immunoreactivity of Bovine Olfactory Receptor Neurons and a Comparison with the Distribution of NADPH-diaphorase Staining: "Wenisch, S., Andressen, C., Derouiche, A., Arnhold, S., Addicks, K., and Leiser, R. (2000). Heme oxygenase-2 and nitric oxide synthase immunoreactivity of bovine olfactory receptor neurons and a comparison with the distribution of nadph-diaphorase staining. The Histochemical Journal, 32(6):381-388."

Nitrite protects against morbidity and mortality associated with tnf- or lps-induced shock in a soluble guanylate cyclase-dependent manner

Cauwels, A., Buys, E. S., Thoonen, R., Geary, L., Delanghe, J., Shiva, S., and Brouckaert, P. (2009). Nitrite protects against morbidity and mortality associated with tnf- or lps-induced shock in a soluble guanylate cyclase-dependent manner. J. Exp. Med., 206(13):2915-2924. http://www.citeulike.org/user/HEIRS/article/6428693

Nitric Oxide Production by the Human Intestinal Microbiota by Dissimilatory Nitrate Reduction to Ammonium

Summary: "the human fecal microbiota were shown to produce NO from trace levels of nitrate under gastrointestinal conditions. Moreover, our data indicate that NO was produced by DNRA and not by denitrification or the L-arginine pathway. Studying the interaction between bacterially produced NO and the host epithelial cells might be pivotal in the etiology of inflammatory diseases of the gastrointestinal tract."


Vermeiren, J., Van de Wiele, T., Verstraete, W., Boeckx, P., and Boon, N. (2009). Nitric oxide production by the human intestinal microbiota by dissimilatory nitrate reduction to ammonium. Journal of Biomedicine and Biotechnology.http://www.citeulike.org/user/HEIRS/article/6056766