Proinflammatory Peptides in Relation to Other Inflammatory Mediators
Sami I. Said in Proinflammatory and Antiinflammatory Peptides, 2020
The kinins, bradykinin, kallidin, and des Arg9-bradykinin, are formed through enzymatic cleavage of their precursors, the kininogens, by various proteases, termed kallikreins (55). Kinins are activated by different stimuli, including injury, inflammation, and low pH. Kinins mediate their biological effects by activating B1 and B2 receptors (56). Chapters 10 and 20 in this book describe in detail the pharmacological and pathophysiological aspects of kinins. Kinins are powerful algesic agents and cause all the main signs of inflammation. In the airways, kinins increase vascular permeability and blood flow, and cause secretion from seromucous glands and bronchoconstriction. There is evidence that kinins produce these effects by activating B2 receptors on effector cells directly. Kinins may also stimulate a variety of cells to release diverse mediators that markedly enhance, or sometimes limit, their own inflammatory action. One of the main proinflammatory pathways by which kinins cause inflammation is stimulation of sensory nerves and release of sensory neuropep-tides. Pharmacological studies in which bradykinin was applied locally to the airways showed that plasma extravasation and bronchoconstriction were mediated by tachykinin release from sensory nerves (57,58).
Rat Thiostatin: Structure and Possible Function in the Acute Phase Response
Andrzej Mackiewicz, Irving Kushner, Heinz Baumann in Acute Phase Proteins, 2020
Two possible physiological functions have to be considered for thiostatin. The first is related to the presence of the sequence for bradykinin in the polypeptide chain of thiostatin. Bradykinin is released from kininogen by the action of kallikrein. One of the recognition sites for this proteinase is at the N-terminal end of the bradykinin segment. In thiostatin, this recognition site differs from that in kininogen by the presence of the residues isoleucine and serine in positions 358 and 359 of the thiostatin polypeptide chain, immediately preceding the N-terminal arginine residue of the bradykinin segment. The evolution of the structure of the thiostatin gene leading to this particular structural feature at the N-terminal end of the bradykinin segment is discussed in Chapter 9 of this volume. The bradykinin moiety of thiostatin, unlike that in the kininogens, cannot be released from the protein by digestion with kallikreins or with low concentrations of trypsin.47 Also, the concentration of kininogens in the blood does not increase during the acute phase response.48 It is therefore unlikely that thiostatin acts as a kininogen. A strong hypotensive effect, such as produced by bradykinin, would be inappropriate during the acute phase response.
Prostate Cancer
Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed in MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Which of the following information on molecular markers in prostate cancer is CORRECT?PCA3, a non-coding RNA, is under expressed in prostate cancer.Ki-67 antigen is detected by immunohistochemical staining and correlates with outcome after radical prostatectomy.Kallikrein 3 level is reduced in metastatic prostate cancer.High molecular weight cytokeratin binds to prostate cancer cells confirming the diagnosis of cancer over HGPIN.PSA doubling time is a useful tool that outperforms total PSA in the diagnosis of prostate cancer.
Emerging drugs for the treatment of diabetic retinopathy
Published in Expert Opinion on Emerging Drugs, 2020
Elio Striglia, Andrea Caccioppo, Niccolò Castellino, Michele Reibaldi, Massimo Porta
Kallikrein is a proteolytic enzyme that splits kininogen into bradychinin. The kallikrein-kinin system is upregulated in DME, as demonstrated by overexpression of B1R and B2R (retinal bradykinin receptors) in retinal vessels in DME [58]. This upregulation increase Nitric Oxide production, which has a vasodilating and permeabilizing effect on the vessel wall, and activation of SRC Kinase, which increase permeability of BRB [59]. KVD001 is a plasma kallicrein inhibitor produced by Kalvista Pharmaceuticals. A phase 2 study (NCT 03466099) is now ongoing to evaluate efficacy, safety, and tolerability of intravitreal administrations in subjects with center-involving DME with previous unsuccessful anti-VEGF treatment. In this study, 129 patients were randomized to three arms (high dose KVD001, low dose KVD001, and sham procedure) to receive four monthly intravitreal injections. The primary outcome is change in BCVA at four months. The secondary outcome is assessment of central subfield thickness. The primary outcome measures show that KVD001 is safe end well-tolerated and although not statistically significant, a trend toward protection is clear in terms of BCVA change and reduction of visual loss [60].
Genetic aspects of idiopathic asthenozoospermia as a cause of male infertility
Published in Human Fertility, 2020
Zohreh Heidary, Kioomars Saliminejad, Majid Zaki-Dizaji, Hamid Reza Khorram Khorshid
Hyperviscosity, or the persistence over time of a homogeneous semen stickiness and adherence, is a less explored infertility-related phenotype that has been thought to negatively impact spermatozoa motility, count and progression in the female reproductive tract, often impairing fertilization (Du Plessis, Gokul, & Agarwal, 2013). Several proteins are known to play key roles in the cascade of semen coagulation and liquefaction including the kallikrein (KLK) family, that was found on chromosome 19q13.3–13.4, and the whey-acidic-protein four-disulfide core domain (WFDC) cluster, located at chromosome 20q13 (Clauss, Lilja, & Lundwall, 2002). Human Kallikreins are a subgroup of serine proteases which are divided into the tissue and plasma kallikreins. The tissue Kallikrein loci encode a family of fifteen closely related serine proteases with pervasive activities in diverse proteolytic cascades; while the plasma kallikrein has no known paralogue and encode only one serine protease (KLKB1). Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation (Michael et al., 2006; Pathak, Wong, Dreveny, & Emsley, 2013).
Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment
Published in Expert Opinion on Investigational Drugs, 2020
Ashay D. Bhatwadekar, Viral S. Kansara, Thomas A. Ciulla
Although the introduction of IVT anti-VEGF-A agents has led to meaningfully improved outcomes in DME, a large unmet need persists, particularly from the treatment burden of frequent IVT injection and incomplete response in some patients [22]. For example, incomplete resolution of macular edema was noted in approximately 1/3 of participants receiving anti-VEGF therapy at 1 and 2 years [23,24]. Furthermore, ‘real world’ studies based on electronic medical records (EMR) and claims data have demonstrated that DME patients may be undertreated, receiving as few as 2–6 IVT anti-VEGF injections in the first year [25–29], with mean gains of only 5 letters on average [27,30]. These limitations have fostered an interest in alternate pathways, including plasma kallikrein. Plasma kallikrein is known to be highly upregulated in vitreous of patients with DME [31], and thus can serve as a target for future drug development. Interestingly the plasma kallikrein pathway may be independent of VEGF, suggesting a potential role in anti-VEGF non-responders. Moreover, inhibition of plasma kallikrein can target a multitude of pathogenic mechanisms involved in DME and DR pathogenesis, such as vascular leakage, neovascularization and inflammation.
Related Knowledge Centers
- Blood Pressure
- Enzyme
- Pancreas
- Plasma Kallikrein
- Semen Analysis
- Serine Protease
- Desquamation
- Sequence Homology
- Prekallikrein
- Factor Xii