,8-IMINAZOLYLETHYLAMINE is the amine which is produced when carbon dioxide is split off from histidine. It was first prepared synthetically by Windaus and Vogt'. Recently Ackermann2 obtained a large yield of the base by submitting histidine to the action of putrefactive organisms. It has been shown that several of the amines thus related to amino-acids possess marked physiological activity. The activity of j8-iminazolylethylamine was discovered in the course of the investigation of ergot and its extracts by G. Barger and one of us3, who attributed this structure to a base which they obtained, and which in minute doses produced tonic contraction of the uterus. The synthetic substance, and the base produced by splitting off carbon dioxide from histidine by bacterial action or by chemical means, were found to have an identical action. Meanwhile Kutscher4 had simultaneously and independently described the isolation from ergot of a base having this action and presumably identical with that obtained by Barger and Dale. By its chemical properties this first ergot base of Kutscher was not distinguishable from 8-iminazolylethylamine; but certain apparent differences in the physiological action of the two bases, observed by Ackermann and Kutscber-5, led them to the conclusion that the ergot base, though closely related to 8-iminazolylethylamine, is not identical with it. The alleged difference in action, on the existence and cause of which our experiments throw light, was as follows: the

The physiological action of β-iminazolylethylamine

https://link.springer.com/content/pdf/10.1016%2Fj.nurt.2010.07.002.pdf

Role of microglia in neurotrauma

Alternatively activated microglia and macrophages in the central nervous system.

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.

/pdf/iron-behaving-badly-inappropriate-iron-chelation-as-a-major-229l082exr.pdf

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

Superoxide dismutases (SODs) are metalloenzymes that play a major role in antioxidant defense against oxidative stress in the body. SOD supplementation may therefore trigger the endogenous antioxidant machinery for the neutralization of free-radical excess and be used in a variety of pathological settings. This paper aimed to provide an extensive review of the possible uses of SODs in a range of pathological settings, as well as describe the current pitfalls and the delivery strategies that are in development to solve bioavailability issues. We carried out a PubMed query, using the keywords "SOD", "SOD mimetics", "SOD supplementation", which included papers published in the English language, between 2012 and 2020, on the potential therapeutic applications of SODs, including detoxification strategies. As highlighted in this paper, it can be argued that the generic antioxidant effects of SODs are beneficial under all tested conditions, from ocular and cardiovascular diseases to neurodegenerative disorders and metabolic diseases, including diabetes and its complications and obesity. However, it must be underlined that clinical evidence for its efficacy is limited and consequently, this efficacy is currently far from being demonstrated.

Superoxide Dismutase Administration: A Review of Proposed Human Uses.

Solid lipid nanoparticles delivering anti-inflammatory drugs to treat inflammatory bowel disease: Effects in an in vivo model

Solid lipid nanoparticles delivering anti-inflammatory drugs to treat inflammatory bowel disease: Effects in an in vivo model.

PPARγ stimulation promotes neurite outgrowth in SH-SY5Y human neuroblastoma cells

Substance P (SP) is a neuropeptide involved in neurogenic inflammation and an agonist for NK1, NK2, and NK3 receptors. SP induces prostaglandin (PG) production in various cell types, and these eicosanoids are responsible for numerous inflammatory and vascular effects.


Cyclooxygenase (COX) are needed to convert arachidonic acid to PGs. The study evaluated the effect of SP on COX expression in human umbilical vein endothelial cells (HUVEC).


COX-2 protein expression was upregulated by SP with a peak at 100 nM and at 20 h; in the same experimental conditions COX-1 protein expression was unchanged. A correlation between COX-2 expression and PGI2 and PGE2 release was detected.


Dexamethasone (DEX) inhibited SP-mediated COX-2 expression. Mitogen-activated protein kinases (MAPK) p38 and p42/44 were activated by SP, whereas SB202190 and PD98059, inhibitors of these kinases, blocked COX-2 expression. 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone (DFU), an experimental selective COX-2 inhibitor, blocked SP-induced PG release.


By RT–PCR and Western blot analysis, we demonstrated that NK1 and NK2 but not NK3 receptors are present on HUVEC. Selective NK1 and NK2 agonists, namely [Sar9, Met(O2)11]SP and [β-Ala8] NKA(4–10), upregulated COX-2 protein expression and PG production, whereas senktide (Suc–Asp–Phe–MePhe–Gly–Leu–Met–NH2), a selective NK3 agonist, was ineffective in this respect. The NK1 selective antagonist L703,606 ((cis)-2-(diphenylmethyl)-N-((2-iodophenyl)-methyl)-1-azabicyclo(2.2.2)octan-3-amine) and the NK2 selective antagonist SR 48,968 ((S)-N-methyl-N-(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4 dichlorophenyl)butyl) benzamide) competitively antagonised SP-induced effects.


The study shows HUVEC to possess functional NK1 and NK2 receptors, which mediate the ability of SP to induce expression of COX-2 in HUVEC, thus showing a previously-undetected effect of SP on endothelial cells.





Keywords: Substance P, cyclooxygenase-2, HUVEC, MAPKs, NK1 receptor, NK2 receptor


Introduction
Substance P (SP) is a neuropeptide belonging to the tachykinin family, a group of regulatory peptides sharing the common C-terminal sequence Phe–X–Gly–Leu–Met–NH2 (Patacchini & Maggi, 1995). Other members of this family found in mammals are neurokinin A (NKA) and neurokinin B (NKB). SP is released from unmyelinated sensory nerve endings, thus evoking inflammatory peripheral effects such as vasodilatation, plasma extravasation and leukocyte activation, which are collectively referred to as ‘neurogenic inflammation' (Foreman & Jordan, 1984; Brunelleschi et al., 1991; Joos & Pauwels, 2000; Dianzani et al., 2001; Harrison & Geppetti, 2001). The effects of tachykinins are mediated by specific G-protein-coupled receptors, of which at least three subtypes have been characterised: NK1, NK2, and NK3. The existence of an NK4 receptor in man has not yet been conclusively demonstrated (Patacchini & Maggi, 1995; Page & Bell, 2002). The mammalian tachykinins display different selectivities for their receptors: SP is more selective for NK1, NKA for NK2, and NKB for NK3 (Regoli et al., 1994). Using selective SP-receptor agonists and antagonists, we recently demonstrated that SP induces PMN adhesion to human umbilical vein endothelial cells (HUVEC) and that this effect is mediated by NK1 and NK2 receptors (Dianzani et al., 2003). In the present study, the presence of SP receptors on HUVEC is investigated by RT–PCR and Western blot techniques; the results confirm that NK1 and NK2 but not NK3 receptors are present on HUVEC.

Cyclooxygenase, known also as prostaglandin H2 synthase (PGHS), is the enzyme that catalyses the first two steps in the biosynthesis of prostaglandins (PGs) from arachidonic acid (Vane et al., 1998). About a decade ago, COX was shown to exist as at least two distinct isoforms, COX-1 and COX-2. COX-1 is responsible for PG and thromboxane production in gastric mucosa and platelets; COX-2 is expressed constitutively in some organs, including the kidney and the brain (Vane et al., 1998).

HUVEC are known to possess both COX isoforms and to display, at Western blot analysis, variable basal levels of COX-2: either no band, or a weakly measurable band. This discrepancy may depend on cell isolation and culture procedures employed in different studies (Hirai et al., 1999; Caughey et al., 2001; Uracz et al., 2002). COX-2 induction in HUVEC has been demonstrated to occur in response to different proinflammatory cytokines, such as IL-1α and β or TNF- α (Caughey et al., 2001; Eligini et al., 2001).

SP evokes the release of PGs from various cell types, including cultured spinal cord astrocytes (Koyama et al., 1999; Marriott et al., 1991), human nasal epithelial cells (Jallat-Daloz et al., 2001) and HUVEC (Alhenc-Gelas et al., 1982; Marceau et al., 1989). However, in the latter study, neither COX expression nor the underlying cell mechanisms were investigated. SP has been shown to stimulate DNA synthesis in several cell types, by activating the p38 and p42/44 mitogen-activated protein kinases (MAPK); this activation is an important signalling mechanism that participates in the development of the inflammatory process (Kyriakis & Avruch, 2001; Yang et al., 2002). MAPKs are involved in regulating PG biosynthesis, and COX-2 induction is associated with their phosphorylation (Guan et al., 1998).

The study addressed the question of whether SP affects COX-2 expression in HUVEC. It investigated time- and dose-dependence of SP-evoked COX-2 expression and of PGI2 (measured as 6-keto-PGF1α) and PGE2 release from HUVEC challenged by SP. The pharmacological modulation of these events was evaluated using dexamethasone (DEX) to modulate gene expression of COX-2, and using 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone (DFU) as experimental selective COX-2 inhibitor. The involvement of p38 and p42/44 MAPKs was evaluated using two inhibitors of these kinases, SB202190 and PD98059. SP-receptors were identified on HUVEC by RT–PCR and Western blot techniques. The effects of SP were characterised in terms of receptors through NK selective agonists and antagonists.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0706660

Substance P-induced cyclooxygenase-2 expression in human umbilical vein endothelial cells

BACKGROUND AND PURPOSE Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, and three subtypes (α, β and γ) have been identified. PPAR activation has been reported to decrease renal injury and markers of glomerular dysfunction in models of renal ischemia/reperfusion (I/R). However, both the I/R effects and the effects of PPAR agonists on podocytes, an integral cellular part of the glomerular filtration barrier, remain to be established.



EXPERIMENTAL APPROACH By using oxygen/glucose deprivation-reoxygenation as an in vitro model that mimics in vivo I/R, the effects of PPAR agonists on podocyte death were compared. Human immortalized podocytes were treated with gemfibrozil, GW0742, pioglitazone or rosiglitazone, as a single or repeated challenge. Cell loss, necrotic and apoptotic cell death were measured.



KEY RESULTS Only the repeated treatment with each PPAR agonist significantly prevented cell death, mainly by decreasing apoptosis. In comparison, in a model of serum deprivation-induced apoptosis, both treatments were effective, although the repeated treatment achieved the more pronounced effect. Finally, our results showed that preservation of Bcl-2, Bax and nephrin expression accompanied the anti-apoptotic effects exerted by PPAR agonists in human podocytes.



CONCLUSION AND IMPLICATIONS These findings contribute to clarification of the pathophysiological role of renal PPARs and suggest that selective PPARα, PPARβ or PPARγ agonists may exert similar protective effects on podocytes by decreasing apoptotic cell death.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2010.01032.x

Arianna Carolina Rosa

Papers

Superoxide Dismutase Administration: A Review of Proposed Human Uses.

Solid lipid nanoparticles delivering anti-inflammatory drugs to treat inflammatory bowel disease: Effects in an in vivo model.

PPARγ stimulation promotes neurite outgrowth in SH-SY5Y human neuroblastoma cells

Substance P-induced cyclooxygenase-2 expression in human umbilical vein endothelial cells

The subtypes of peroxisome proliferator-activated receptors expressed by human podocytes and their role in decreasing podocyte injury