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Pulsed Electromagnetic Fields
Published in Marko S. Markov, James T. Ryaby, Erik I. Waldorff, Pulsed Electromagnetic Fields for Clinical Applications, 2020
PEMF signals with a vast range of waveform parameters have been reported to reduce pain and inflammation (Ross and Harrison, 2013b) and enhance healing (Pilla, 2006). Using the ECM model, a common unifying mechanism has been proposed, which involves Ca2+-dependent NO signaling, to quantify the relation between signal parameters and bioeffect (Pilla et al., 2011). Intracellular calcium ions play an important role in the signal transduction pathways a cell utilizes to respond to external challenges, for example, cell growth and division, apoptosis, metabolism, synaptic transmission, and gene expression (Bootman et al., 2001; Mellstrom et al., 2008). Regulation of cytosolic Ca2+ concentration is orchestrated by an elaborate system of pumps, channels, and binding proteins found both in the plasma membrane and on intracellular organelles such as the endoplasmic reticulum (Harzheim et al., 2010). High-affinity proteins (e.g., CaM, troponin) mediate the multiple physiological responses regulated by changes in intracellular Ca2+ concentrations produced by challenges that cause free Ca2+ to increase above its normal and tightly regulated value of approximately 100 nM in mammalian cells (Konieczny et al., 2012). In terms of PEMF mechanism, CaM is of particular interest because it is the first responder to changes in cytosolic Ca2+ and because of the many roles it plays in cell signaling and gene regulation pathways once activated by bound Ca2+ (Faas et al., 2011). In an immediate response to stress or injury, activated CaM binds to its primary enzyme target, constitutive nitric oxide synthase (cNOS, neuronal [nNOS], and/or endothelial [eNOS]), which, in turn, binds to and catalyzes L-arginine resulting in the release of the signaling molecule NO. As a gaseous free radical with an in-situ half-life of about 5 s (Ignarro et al., 1993), NO can diffuse through membranes and organelles and act on molecular targets at distances up to about 200 µm (Tsoukias, 2008). Low transient concentrations of NO activate its primary enzyme target, soluble guanylyl cyclase (sGC), which catalyzes the synthesis of cyclic guanosine monophosphate (cGMP) (Cho et al., 1992). The CaM/NO/cGMP signaling pathway is a rapid response cascade that can modulate peripheral and cardiac blood flow in response to normal physiologic demands as well as to inflammation and ischemia (Bredt and Snyder, 1990). This same pathway also modulates the release of cytokines, such as interleukin-1beta (IL-1β), which is proinflammatory (Ren and Torres, 2009), and growth factors, such as basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF), which are important for angiogenesis, a necessary component of tissue repair (Werner and Grose, 2003).
Computational modeling of inhibitory signal transduction in urinary bladder PDGFRα+ cells
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2023
Amritanshu Gupta, Rohit Manchanda
In animal models, it has been demonstrated that nitric oxide (NO) induces dSMC relaxation, and the application of nitric oxide synthase (NOS) inhibitors reduced detrusor contractions (Mumtaz et al. 2000; Mamas et al. 2003). NO acts in target tissues via the nitric oxide-soluble guanyl cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway. However, in isolated guinea pig bladder preparations, the application of the NO donor sodium nitroprusside did not raise cyclic guanosine monophosphate (cGMP) levels in the dSMCs suggesting the involvement of an indirect pathway for mediation of NO-induced relaxation (Gillespie and Drake 2004). This indirect pathway could be via NO action on PDGFRα+ cells, which express the nitric oxide sensitive soluble guanylyl cyclase (NO-sGC) and exhibit intense cGMP immunoreactivity (Blair et al. 2014).
Nitric oxide release from a photoactive water-soluble ruthenium nitrosyl. Biological effects
Published in Journal of Coordination Chemistry, 2018
Meredith A. Crisalli, Lilian P. Franco, Bruno R. Silva, Alda K. M. Holanda, Lusiane M. Bendhack, Roberto S. Da Silva, Peter C. Ford
This study has described a photo-activated NO releasing moiety Ru(salenCO2H)(NO)Cl (1) that is stable in aerobic aqueous solutions while displaying pH dependent quantum yields for NO generation in vitro. This complex was shown to stimulate vasodilation in mammalian aortic rings specifically when exposed to ambient light. The pH-dependent quantum yields can be attributed to the nitrosyl/N-nitrito equilibrium that results in enhanced NO release at lower pH. Such an effect suggests a strategy for targeting NO release in the relatively acidic environment characteristic of hypoxic tumors [43, 44]. Neither the photoNORM precursor nor the small amount of NO released is cytotoxic, but the photo-induced NO release, even with a very modest quantum yield, would be sufficient to trigger soluble guanylyl cyclase mediated vasodilation [45], thereby increasing circulation to and oxygenation of the targeted tissues. If this process were coupled to radiotherapy, the increased oxygenation would enhance the sensitivity of the targeted tissues to radiation-induced cell death. Similarly, such targeted NO release leading to enhanced circulation could synergistically enhance the efficacy of chemotherapy.