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Cellular Regulation of Kinin Receptors
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Adelbert A. Roscher, Alexander Faussner
Functional effects of BK, mediated via B2receptors, are shown to be potentiated by co-administration of PGE2, PGI2, calcitonin gene-related peptide, 5-hydroxy-tryptamine, substance P, IL-1, or platelet-activating factor (27,75). IL-1 and PAF are both able to increase B2 receptor synthesis and expression, leading to enhanced responsiveness to BK (27,76 and data in this report). In many cell types, PGE2 and PGI2 elicit a marked accumulation of cAMP, which in turn might directly promote B2 receptor expression via the cAMP-responsive elements, recently identified in the B2 receptor gene promoter (63). TNF, PGE2, and cAMP have also been shown to upregulate the expression of kininogens on cell surface receptors (24), which points to an additional mechanism that may facilitate the delivery of BK at sites of inflammation.
Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
An analysis of how kininogens may participate in the acute phase response is complicated by their reported multiple roles. The human kinogens are apparently (1) able to participate in the intrinsic coagulation system, (2) serve as precursors for the generation of kinins, and (3) inhibit cysteine proteinases of the papain superfamily. In all species studied, H-kininogen and L-kininogen are products of the same gene;124 they contain identical cystatin domains and kinin segments, but diverge in their C-terminal regions as a result of alternate exon splicing. H-kininogen participates in the intrinsic coagulation pathway by modifying the events that lead to activation of prokallikrein and factors XI and XII.125 L-kininogen cannot substitute for H-kininogen in this function, although both are equivalent substrates for the excision of kinins by tissue or plasma kallikreins.
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
There is a complex relationship among the activation of Factor XII, activation of Factor XI, formation of plasmin, formation of kallikrein, and the effect of high-molecular weight kininogen (Figure 23). Subjects with prekallikrein deficiency elicit no special symptoms, but their blood exerts a prolonged clotting time in vitro. They show a defective surface-mediated activation of fibrinolysis and defective permeability enhancement.397,499 In this disease condition kallikrein accelerates the activation of Factor XII and Factor VII, and enhances the conversion of kininogen to bradykinin.245 A defect in kininogen production is due to the deficiency of high-molecular weight kininogen, and it prolongs clotting time in vitro, with an impaired generation of the vascular permeability factor. Various steps involved in blood coagulation and vascular alterations are presented in a scheme (Figure 24).
A focus on the use of subcutaneous C1-inhibitor for treatment of hereditary angioedema
Published in Expert Review of Clinical Immunology, 2020
Maria Fernanda Villavicencio, Timothy Craig
The initial work on SC-C1-INH was [6] an early phase trial to compare pharmacokinetics (PK), pharmacodynamics (PD), and safety of SC human pasteurized C1-INH concentrate compared with IV administration. A single dose of 1000 U in 24 patients with mild to moderate HAE age ≥17 was used and blood samples after treatment were taken at different hours up to 7 days after treatment. The results demonstrated a mean maximum C1-INH functional increase of 33.8% after IV administration and of 9.8% after SC administration. The bioavailability of SC administration was 39.7%. The SC C1-INH had a slower increase of C1-INH activity, lower Cmax (maximum plasma concentration) and markedly delayed Tmax (time to maximum activity) for C1-INH antigen and C4 antigen levels [6]. A decrease in cleaved high-molecular-weight kininogen (cHK) from 44.8% to 42% was also demonstrated. The SC-C1-INH therapy was tolerated well with few adverse events other than injection site reactions. In summary, this study demonstrated the feasibility of using SC C1-INH concentrate for treatment of HAE [6]. See Table 2.
Advances in the proteomics of amniotic fluid to detect biomarkers for chromosomal abnormalities and fetomaternal complications during pregnancy
Published in Expert Review of Proteomics, 2019
Aayushi Vasani, Maushmi S. Kumar
IUGR is a condition of an unborn baby, being smaller due to less growth rate than a normal baby inside the womb. IUGR carries an increased risk of mortality and morbidity. Identification is crucial because proper evaluation and management can result in favorable outcomes. Decreased IUG may have a negative effect on brain and mental development [59]. First attempt on proteomics approach of IUGR has been done in 1998 where they discovered reduced glycosylation of 2HS glycoprotein in cord plasma [60]. Proteins like transferrin cause Cu and Fe metabolism, and ceruloplasmin acts as circulating ferroxidase enzyme able to oxidize ferrous ions together acting as anti-oxidative system [61]. Down-regulation of both proteins causes fetal growth retardation [62]. High blood ferritin levels can also be a cause of IUGR [63]. It was observed that fibrinogen was up-regulated in the amniotic fluid which causes obstetric complications during pregnancy forming clots in the body [64]. Alpha-2-macroglobulin (α2M) which causes coagulation was also detected [65,66]. Due to the immune response in the body, there are a cascade of complement proteins like C3, C3b, C3c, and C4 participating in innate immunity and are crucial intermediates in the first trimester. Proteins controlling blood pressure, and iron copper homeostasis show some abnormality. For blood pressure, angiotensinogen is up-regulated and kininogen is down-regulated in the first 20 weeks of gestation [67,68].
A structure–function analysis in patients with prekallikrein deficiency
Published in Hematology, 2018
Antonio Girolami, Silvia Ferrari, Elisabetta Cosi, Anna Maria Lombardi
The contact phase of blood coagulation is composed of three main factors, namely FXII, prekallikrein (PK) and Factor XI. High-molecular-weight kininogen (HMWK) also participates in the process as a co-factor. A central role is played by FXII, which, once activated, activates both PK and FXI. PK, once activated to kallikrein by aFXII, plays a role in controlling blood pressure by cleaving HMWK and releasing bradykinin. PK will also activate tissue plasminogen activator and therefore stimulate fibrinolysis [1]. These are the two main functions of PK, namely vasodilatation with consequent hypotension and increased fibrinolysis. Both functions may have a great potential role in vascular physiology and pathology. FXI, once activated, initiates, instead, the intrinsic clotting system by activating FIX. PK structure is similar to that of FXI and this explains why they are both activated by aFXII. There are also differences since PK is not activated by thrombin. Furthermore, PK, once activated, has the capability of enhancing FXII activation. FXI, on the contrary, lacks these two properties [1]. Therefore, it appears that PK plays an important role in the contact system. It has no clotting capability but it may cause vasodilatation, decrease blood pressure, stimulate fibrinolysis and serve as a potentiating effect in the activation of FXII [1–3].