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Abstract Objective Patients with rheumatoid arthritis (RA) have shown increased levels of neutrophils generating kallikrein-kinin peptides in blood which are potent mediators of inflammation. This study investigated the association between the bioregulation of kinin-mediated inflammation with the clinical, quality of life, and imaging characteristics (e.g. ultrasonography) of different arthritides. Methods Patients with osteoarthritis (OA, n = 29), gout (n = 10) and RA (n = 8) were recruited and screened for clinical symptoms, quality of life, and ultrasonographical assessment of arthritis. Blood neutrophils were assessed for the expression of bradykinin receptors (B1R and B2R), kininogens and kallikreins by immunocytochemistry with visualization by bright field microscopy. Levels of plasma biomarkers were measured by ELISA and cytometric bead array. Results Quality of life (SF-36 domains and summary scores; including pain; and, HAQ) was similar across OA, gout and RA patients; with the exception of worse physical functioning scores between OA and gout patients. Synovial hypertrophy (on ultrasound) differed between groups (p = 0.001), and the dichotomised Power Doppler (PD) score of greater than or equal to 2 (PD-GE2) was marginally significant (p = 0.09). Plasma IL-8 were highest in patients with gout followed by RA and OA (both, P

While coronavirus disease 2019 (COVID-19) begins as a respiratory infection, it progresses as a systemic disease involving multiorgan microthromboses that underly the pathology. SARS-CoV-2 enters host cells via attachment to the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is widely expressed in a multitude of tissues, including the lung (alveolar cells), heart, intestine, kidney, testis, gallbladder, vasculature (endothelial cells), and immune cells. Interference in ACE2 signaling could drive the aforementioned systemic pathologies, such as endothelial dysfunction, microthromboses, and systemic inflammation, that are typically seen in patients with severe COVID-19. ACE2 is a component of the renin–angiotensin system (RAS) and is intimately associated with the plasma kallikrein-kinin system (KKS). As many papers are published on the role of ACE and ACE2 in COVID-19, we will review the role of bradykinin, and more broadly the KSS, in SARS-CoV-2-induced vascular dysfunction. Furthermore, we will discuss the possible therapeutic interventions that are approved and in development for the following targets: coagulation factor XII (FXII), tissue kallikrein (KLK1), plasma kallikrein (KLKB1), bradykinin (BK), plasminogen activator inhibitor (PAI-1), bradykinin B1 receptor (BKB1R), bradykinin B2 receptor (BKB2R), ACE, furin, and the NLRP3 inflammasome. Understanding these targets may prove of value in the treatment of COVID-19 as well as in other virus-induced coagulopathies in the future. [ABSTRACT FROM AUTHOR]

Abstract The Chinese Center for Disease Control and Prevention reported 80% of coronavirus infections were mild cases; hence, most cases will be managed in an outpatient setting. COVID‐19 is associated with a hypercoagulable state; therefore, further research should be done on outpatient use of anticoagulation for VTE/PE prophylaxis in these patients.

The Chinese Center for Disease Control and Prevention reported 80% of coronavirus infections were mild cases; hence, most cases will be managed in an outpatient setting. COVID‐19 is associated with a hypercoagulable state; therefore, further research should be done on outpatient use of anticoagulation for VTE/PE prophylaxis in these patients. [ABSTRACT FROM AUTHOR]

This study is performed to study the positive effects and benefits of going green and creating green physical environments of work on health promotion and stressors reduction on workers in Sympathoadrenal and Kallikrein-Kinin Systems. It also evaluates environmental conditions of work-place, as well as sympathoadrenal and kallikrein-kinin systems for early (prenosological) sings of de-adaptation to workrelated stressors in workers engaged in non-ferrous metallurgy. Workplace health promotion (WHP) has been proposed as a preventive intervention for stress, possibly operating by promoting positive organizational culture or via programs promoting healthy lifestyles. In order to do this a trial experiment was done on animals (white rats). Adrenaline and noradrenaline (AD and NAD) levels in the liver, adrenal glands and hearts of rats were measured throughout 2, 4 and 12 trial weeks. Changes in sympathoadrenal system, detected in workers, who were working at the main workshops for a long time, reflect all the stages of nonspecific adaptation process to work-place environment, defined as a standard activation of stress-realizing system. At the last stages of stress, the KKS, which represents a cascade, promotes body resistance to workrelated stressors and negative environmental conditions. Signs of early de-adaptation were found in healthy workers to identify who of them are at risk of adaptive breakdown. Our tests were used at five times as part of health examination, and some related guidelines were published. [ABSTRACT FROM AUTHOR]

The plasma contact system sits atop the intrinsic coagulation cascade and plasma kallikrein-kinin pathway, and in vivo its activation contributes, respectively, to coagulation and inflammation mainly via two downstream pathways. This system has been widely investigated, its activation mechanisms by negatively charged surfaces and the interactions within its components, factor XII, prekallikrein and high molecular weight kininogen are well understood at the biochemical level. However, as most of the activators that have been discovered by in vitro experiments are exogenous, the physiological activators and roles of the contact system have remained unclear and controversial. In the last two decades, several physiological activators have been identified, and a better understanding of its roles and its connection with other signaling pathways has been obtained from in vivo studies. In this article, we present an overview of the contact pathway with a focus on the activation mechanisms, natural stimuli, possible physiological roles, potential risks of its excessive activation, remaining questions and future prospects. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a common complication of both type 1 and type 2 diabetes and is the leading cause of blindness in people of working age. Current treatment strategies are mostly limited to laser photocoagulation, which restricts proliferative retinopathic changes but also causes irreversible damage to the retina. This review examines two important pathways involved in regulating vascular function and their role in the development of diabetic retinopathy. One, the renin-angiotensin system, is well known and has established angiogenic effects on the retina that increase in diabetic retinopathy. The other, the kallikrein-kinin system, has recently been found to be important in the development of diabetic retinal complications. This review describes the components of the two signalling networks, examines the current animal model studies investigating the role of these pathways in diabetic retinopathy and reviews the clinical studies that have been undertaken examining systemic inhibition of different points in these pathways. These systems are promising targets for therapies aimed at inhibiting the development of diabetic retinopathy and in the future, combination therapies that take advantage of both pathways might result in new treatment options for this debilitating complication of diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Regulation of the kallikrein–kinin system in cerebral inflammation is still unclear. Here, we used reverse-transcription polymerase chain reaction (RT-PCR) techniques to show that lipopolysaccharide (LPS) activates the kallikrein–kinin system by enhancing liberation of bradykinin (BK), and alters mRNA levels of kallikrein–kinin system components, including high molecular weight (H-) and low molecular weight (L-) kininogens, in ECPC4 cells, a cell line of mouse choroid plexus epithelium. LPS treatment increased liberation of immunoreactive bradykinin in the supernatant of ECPC4 cells, and addition of LPS (500ng/ml) to cultures resulted in elevation of H- and L-kininogen mRNA levels in ECPC4 cells within 24–48h. Furthermore, LPS treatment elevated bradykinin type 2 and type 1 receptor mRNA levels within 4h, but did not change tissue kallikrein or plasma kallikrein mRNA levels. On the other hand, expression of pro-inflammatory mediators interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 mRNA increased within 4–8h after addition of LPS to ECPC4 cells. The addition of IL-1β and TNF-α to investigate the major mediator for kininogen expression in ECPC4 cells remarkably induced expression of H- and L-kininogen mRNAs in ECPC4 cells. These results suggest that LPS activates the kallikrein–kinin system in the choroid plexus via autocrine induction of IL-1β and TNF-α. [Copyright &y& Elsevier]

Hemoglobin vesicles (HbVs), cellular-type artificial oxygen carriers containing human hemoglobin, were assessed for their biocompatibility by mixing with human plasma in vitro . Among three kinds of HbVs (PEG-DPEA-HbV, PEG-DPPG-HbV and DPPG-HbV), PEG-DPEA-HbV did not affect the extrinsic or intrinsic coagulation activities of the plasma, while PEG-DPPG-HbV and DPPG-HbV tended to shorten the intrinsic coagulation time. The kallikrein-kinin cascade of the plasma was slightly activated by PEG-DPPG-HbV and DPPG-HbV, but not by PEG-DPEA-HbV. The complement consumption of the plasma was observed by incubation with DPPG-HbV, but not with PEG-DPEA-HbV or PEG-DPPG-HbV. These results indicate that PEG-DPEA-HbV has a higher biocompatibility with human plasma. [ABSTRACT FROM AUTHOR]

Forty-five relatives of 4 families with hereditary angioneurotic edema (HANE) were studied. Twenty-five, including 11 asymptomatic kindreds with the disposition, showed typical changes in complement system compatible with HANE. Follow-up study of HANE patients showed that, even in remission period, complement, coagulation and fibrinolytic systems can be activated. During edema attacks, moderate haemoconcentration and neutrophilia were encountered and kallikrein-kinin system was found to be also activated. Replacement therapy with C $$\bar l$$ -inhibitor preparation for an edema attack revealed that clinical improvement paralleled the increase in blood levels of high molecular weight kininogen. Thus, HANE attack is considered to be elicited in kindreds with the hereditary disposition by activation of plasma protease systems, particularly by that of kallikrein-kinin system. On the other hand, exogenous triggers that can initiate activation of the protease systems can be classified into 2, neuro-humoral (sympathetic nerve response) and physico-chemical, categories. Hence, the edema attack of kindreds with the hereditary disposition can at least be modified by the biosynthesis of plasma factors and the individual susceptibility to the liberated catecholamines. These two different reaction processes are considered to be linked by the release of plasminogen activator and/or Hageman factor activating enzyme. [ABSTRACT FROM AUTHOR]

This paper provides a brief historical sketch of the science of biologically active peptides. It also offers the story of how Ervin G. Erdös, a pioneer in the study of metabolism of various peptides, influenced me through collaborations that span many years. I worked in Dr. Erdös's research laboratories in Oklahoma City, Dallas, and Chicago, and we shared research interests through visits across the Atlantic between the former Yugoslavia and the United States. Among other findings, we discovered angiotensin-converting enzyme in the retina, which opened up a new research direction for many scientists interested in serious ocular diseases. This tribute to my mentor paints a portrait of a man who, in addition to his dedication to science and his seminal discoveries about the metabolism of peptides, took the time to invest in training many young scientists. His fine personal qualities explain why all of those who worked with him hold him in such high regard., Competing Interests: The author declares that he has no conflicts of interest with the contents of this article., (© 2018 Igić.)