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Human H-kininogen (120 kDa) plays a role in many pathophysiological processes and interacts with the cell surface through protein receptors and proteoglycans, which mediate H-kininogen endocytosis. In the present work we demonstrate that H-kininogen containing bradykinin domain is internalized and different endogenous kininogenases are present in C...
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The unpredictable nature of attacks of tissue swelling in hereditary angioedema requires the identification of reliable biomarkers to monitor disease activity as well as response to therapy. At present, one can assess a C4 level (by ELISA) to assist in diagnosis but neither C4 nor C1 inhibitor levels reflect clinical course or prognosis. We will he...
Citations
... 238 Bradykinin is a proinflammatory peptide synthesized from an inactive pre-protein kininogen through stimulation by the serine protease kallikrein (KLK). 241,242 KLK is characterized by a group of serine proteases (KLK1-KLK15) found in several tissues; KLKB1 is usually found in the pancreas and is responsible for plasma kallikrein. 243,244 Furthermore, bradykinin serum level is ...
Abstract: The global pandemic from COVID-19 infection has generated significant public
health concerns, both health-wise and economically. There is no specific pharmacological
antiviral therapeutic option to date available for COVID-19 management. Also, there is an
urgent need to discover effective medicines, prevention, and control methods because of the
harsh death toll from this novel coronavirus infection. Acute respiratory tract infections,
significantly lower respiratory tract infections, and pneumonia are the primary cause of
millions of deaths worldwide. The role of micronutrients, including trace elements, boosted
the human immune system and was well established. Several vitamins such as vitamin A,
B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and
copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays
essential physiological roles in promoting the immune system. Furthermore, zinc is an
indispensable microelement essential for a thorough enzymatic physiological process. It
also helps regulate gene-transcription such as DNA replication, RNA transcription, cell
division, and cell activation in the human biological system. Subsequently, zinc, together
with natural scavenger cells and neutrophils, are also involved in developing cells responsible
for regulating nonspecific immunity. The modern food habit often promotes zinc
deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently
diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes
patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe
acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency
virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the
various roles played by zinc in the management of COVID-19 infection.
... 238 Bradykinin is a proinflammatory peptide synthesized from an inactive pre-protein kininogen through stimulation by the serine protease kallikrein (KLK). 241,242 KLK is characterized by a group of serine proteases (KLK1-KLK15) found in several tissues; KLKB1 is usually found in the pancreas and is responsible for plasma kallikrein. 243,244 Furthermore, bradykinin serum level is ...
Abstract: The global pandemic from COVID-19 infection has generated significant public
health concerns, both health-wise and economically. There is no specific pharmacological
antiviral therapeutic option to date available for COVID-19 management. Also, there is an
urgent need to discover effective medicines, prevention, and control methods because of the
harsh death toll from this novel coronavirus infection. Acute respiratory tract infections,
significantly lower respiratory tract infections, and pneumonia are the primary cause of
millions of deaths worldwide. The role of micronutrients, including trace elements, boosted
the human immune system and was well established. Several vitamins such as vitamin A,
B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and
copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays
essential physiological roles in promoting the immune system. Furthermore, zinc is an
indispensable microelement essential for a thorough enzymatic physiological process. It
also helps regulate gene-transcription such as DNA replication, RNA transcription, cell
division, and cell activation in the human biological system. Subsequently, zinc, together
with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc
deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently
diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes
patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe
acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency
virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the
various roles played by zinc in the management of COVID-19 infection.
... 238 Bradykinin is a proinflammatory peptide synthesized from an inactive pre-protein kininogen through stimulation by the serine protease kallikrein (KLK). 241,242 KLK is characterized by a group of serine proteases (KLK1-KLK15) found in several tissues; KLKB1 is usually found in the pancreas and is responsible for plasma kallikrein. 243,244 Furthermore, bradykinin serum level is ...
... 238 Bradykinin is a proinflammatory peptide synthesized from an inactive pre-protein kininogen through stimulation by the serine protease kallikrein (KLK). 241,242 KLK is characterized by a group of serine proteases (KLK1-KLK15) found in several tissues; KLKB1 is usually found in the pancreas and is responsible for plasma kallikrein. 243,244 Furthermore, bradykinin serum level is ...
Nandeeta Samad,1 Temitayo Eniola Sodunke,2 Abdullahi Rabiu Abubakar,3 Iffat Jahan,4 Paras Sharma,5 Salequl Islam,6 Siddhartha Dutta,7 Mainul Haque8 1Department of Public Health, North South University, Dhaka, 1229, Bangladesh; 2Department of Anatomy, University of Ilorin, Ilorin, Kwara State, Nigeria; 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Bayero University, Kano, 700233, Nigeria; 4Department of Physiology, Eastern Medical College, Cumilla, Bangladesh; 5Department of Pharmacognosy, BVM College of Pharmacy, Gwalior, India; 6Department of Microbiology, Jahangirnagar University, Dhaka, 1342, Bangladesh; 7Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 8The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, MalaysiaCorrespondence: Mainul HaqueUnit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur, 57000, MalaysiaTel +60 10 926 5543Email runurono@gmail.comAbstract: The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.Keywords: zinc therapy, microelement, immune-boosting, efficacy, COVID-19, viral infections, pneumonia, pandemic
... 37 Further evidence supporting a potentially specific role of HS in localizing HK to the cellular surface comes from experiments that show reduced surface HK surface binding in the presence of soluble HS in rabbit aorta endothelial cells. 38 A potential mechanism for how HS could influence bradykinin cleavage on the cellular surface is through defects in cellular uptake; it has been shown that HS proteoglycans mediate endocytosis of HK, 39,40 which could have potential influence on bradykinin generation and/or targeting. This leads us to the following hypothesis regarding the effect of the HS3ST6 mutation on angioedema formation in the patients with HAE who belonged to the family described in this study. ...
Background
Hereditary angioedema (HAE) is a potentially fatal disorder resulting in recurrent attacks of severe swelling. It may be associated with a genetic deficiency of functional C1 inhibitor (C1-INH) or with normal C1-INH (HAEnCI). In families with HAEnCI, HAE-linked mutations in the F12, PLG, KNG1, ANGPT1, or MYOF genes have been identified. In many families with HAEnCI the genetic cause of the disease is currently unknown.
Objective
The aim of this study was to identify a novel disease-linked mutation for HAEnCI.
Methods
Methods comprised whole exome sequencing (WES), Sanger sequencing analysis, pedigree analysis, bioinformatical analysis of the mutation, and biochemical analysis of parameters of the kallikrein-kinin (contact) system.
Results
By performing WES on a multi-generation family with HAEnCI we identified the HS3ST6 mutation c.430A>T (p.Thr144Ser) in all three affected family members that were sequenced. This gene encodes the heparan sulfate glucosamine 3-O-sulfotransferase 6 (3-OST-6) which is involved in the last step of heparan sulfate biosynthesis. The p.Thr144Ser mutation is likely to affect the interaction between two beta sheets stabilizing the active center of the 3-OST-6 protein.
Conclusions
We conclude that mutant 3-OST-6 fails to transfer sulfo groups to the 3-OH position of heparan sulfate, resulting in incomplete heparan sulfate biosynthesis. This is likely to affect cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development.
... The current research group is the first to show that the interaction of H-kininogen and PK on the cell surface mediated by HSPGs results in endocytosis ( [66][67][68]; Figure 1). Hkininogen interacts with cellular sites in either RAECs or epithelial CHO cells, wild type CHO-K1 cells and CHO-745 cells, mutant cells deficient in xylosyltransferase and as consequence is involved in GAG biosynthesis. ...
... The endocytosis process of H-kininogenin CHO-K1 cells is disrupted by pretreatment of the cells using chloroquine, an alkalinizing agent of acid endosomes; cholesterol depletion by methyl-β-cyclodextrin also inhibits endocytosis; the endocytosis of Hkininogen is independent of transferrin endocytosis, strongly indicating that the endocytosis of H-kininogen is not dependent on clathrin. The membrane lipid raft domains/caveolae mediate the endocytotic process of H-kininogen, as the colocalization of H-kininogen with caveolin-1 has been demonstrated [66,68]. ...
... In contrast, CHO-745 cells, which are almost completely devoid of GAGs, do not take up intact H-kininogen; the inhibition of GAG sulfation blocks the endocytosis process, and the integrity of H-kininogen is very important for internalization since BKfree H-kininogen does not become internalized [67,68]. ...
... The H-kininogen and its fragments were detected using primary monoclonal antibody anti-kininogen D6, HKL1 dilution 1 : 1000 (anti-D6 HK), and horseradish peroxidase (HRP) conjugated goat anti-mouse IgG (IgG-HRP) secondary antibody dilution 1 : 1500 (catalog#A0168, Sigma-Aldrich, RRID: AB-257867) after which chemiluminescence was measured. Both intact H-kininogen and HKa were used as controls, which corresponded to intact H-kininogen incubated with human plasma kallikrein (1 : 1 molar ratio) (Damasceno et al. 2015). The PKal was detected using primary anti-PKal antibody (U-691.10, ...
Temporal lobe epilepsy (TLE) is a chronic disease, characterized by severe and refractory seizures, triggered in the hippocampus and/or amygdala, disrupting the blood–brain barrier. This disruption can sustain, or aggravate, the epileptic condition. The aim of this study was to evaluate the activation of the kallikrein‐kinin system in patients with TLE, as it relates to the maintenance of blood–brain barrier. Human hippocampal sclerotic tissues removed after surgery for seizure control, plasma, and serum were used in the following assays: immunostaining for white blood cells in the TLE hippocampus, C‐reactive protein in serum, quantification of plasma kallikrein (PKal) and cathepsin B (CatB) activity in serum and plasma, quantification of C1‐inhibitor, analysis of high‐molecular‐weight kininogen (H‐kininogen) fragments, and activation of plasma prekallikrein for comparison with healthy controls. Infiltration of white blood cells in the sclerotic hippocampus and a significant increase in the neutrophil/lymphocyte ratio in the blood of TLE patients were observed. High levels of C‐reactive protein (TLE = 1.4 ± 0.3 µg/mL), PKal (TLE = 5.4 ± 0.4 U/mL), and CatB (TLE = 4.9 ± 0.4 U/mL) were also evident in the serum of TLE patients comparing to controls. A strong linear correlation was observed between active CatB and PKal in the serum of TLE patients (r = 0.88). High levels of cleaved H‐kininogen and free PKal, and low levels of C1‐inhibitor (TLE = 188 ± 12 µg/mL) were observed in the serum of TLE patients. Our data demonstrated that the plasma kallikrein‐kinin system is activated in patients with TLE.
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... The non-bioluminescence MDA-MB-231 indicate the presence of at least one of these receptors (B1R) [47,50], suggesting they are likely to be present in the bioluminescent line as well. Cancer cell lines vary in their production of HMWK [50][51][52]. Importantly, in the percentiles, *P < 0.05; **P < 0.01; ***P < 0.001 compared to control current study we demonstrate that this basal release of HMWK increase rapidly (within 1 h) after exposure to all three tested NPs. ...
Background
Metastatic cancer to bone is well-known to produce extreme pain. It has been suggested that the magnitude of this perceived pain is associated with disease progression and poor prognosis. These data suggest a potential cross-talk between cancer cells and nociceptors that contribute not only to pain, but also to cancer aggressiveness although the underlying mechanisms are yet to be stablished.
Methods
The in vitro dose dependent effect of neuropeptides (NPs) (substance P [SP], calcitonin gene-related peptide and neurokinin A [NKA]) and/or its combination, on the migration and invasion of MDA-MB-231LUC+ were assessed by wound healing and collagen-based cell invasion assays, respectively. The effect of NPs on the expression of its receptors (SP [NK1] and neurokinin A receptors [NK2], CALCRL and RAMP1) and kininogen (high-molecular-weight kininogen) release to the cell culture supernatant of MDA-MB-231LUC+, were measured using western-blot analysis and an ELISA assay, respectively. Statistical significance was tested using one-way ANOVA, repeated measures ANOVA, or the paired t-test. Post-hoc testing was performed with correction for multiple comparisons as appropriate.
Results
Our data show that NPs strongly modify the chemokinetic capabilities of a cellular line commonly used as a model of metastatic cancer to bone (MDA-MB-231LUC+) and increased the expression of their receptors (NK1R, NK2R, RAMP1, and CALCRL) on these cells. Finally, we demonstrate that NPs also trigger the acute release of HMWK (Bradykinin precursor) by MDA-MB-231LUC+, a molecule with both tumorigenic and pro-nociceptive activity.
Conclusions
Based on these observations we conclude that NPs exposure modulates this breast cancer cellular line aggressiveness by increasing its ability to migrate and invade new tissues. Furthermore, these results also support the pro nociceptive and cancer promoter role of the peripheral nervous system, during the initial stages of the disease.
... The current research group is the first to show that the interaction of H-kininogen and PK on the cell surface mediated by HSPGs results in endocytosis (Melo et al., 2009;Veronez et al., 2014;Damasceno et al., 2015 ; Figure 1). H-kininogen interacts with cellular sites in either RAECs or epithelial CHO cells, wild type CHO-K1 cells and CHO-745 cells, mutant cells deficient in xylosyltransferase and as consequence is involved in GAG biosynthesis. ...
... The endocytosis process of H-kininogenin CHO-K1 cells is disrupted by pretreatment of the cells using chloroquine, an alkalinizing agent of acid endosomes; cholesterol depletion by methyl-βcyclodextrin also inhibits endocytosis; the endocytosis of Hkininogen is independent of transferrin endocytosis, strongly indicating that the endocytosis of H-kininogen is not dependent on clathrin. The membrane lipid raft domains/caveolae mediate the endocytotic process of H-kininogen, as the colocalization of H-kininogen with caveolin-1 has been demonstrated (Melo et al., 2009;Damasceno et al., 2015). ...
... In contrast, CHO-745 cells, which are almost completely devoid of GAGs, do not take up intact H-kininogen; the inhibition of GAG sulfation blocks the endocytosis process, and the integrity of H-kininogen is very important for internalization since BK-free H-kininogen does not become internalized (Veronez et al., 2014;Damasceno et al., 2015). ...
Human plasma kallikrein-kinin system proteins are related to inflammation through bradykinin. In the proximity of its target cells, high molecular weight kininogen (H-kininogen) is the substrate of plasma kallikrein, which releases bradykinin from H-kininogen. Heparan sulfate proteoglycans (HSPGs) play a critical role in either recruiting kinin precursors from the plasma, or in the assembly of kallikrein-kinin system components on the cell surface. Furthermore, HSPGs mediate the endocytosis and activation of H-kininogen and plasma prekallikrein. In the presence of HSPGs (Chinese hamster ovary cell, CHO-K1, wild type cells) both heparin and heparan sulfate strongly inhibit the H-kininogen interaction with the cell membrane. H-kininogen is internalized in endosomal acidic vesicles in CHO-K1 but not in CHO-745 cells (mutant cells deficient in glycosaminoglycan biosynthesis). The endocytosis process is lipid raft-mediated and is dependent on caveolae. Both types of CHO cells do not internalize bradykinin-free H-kininogen. At pH 7.35, bradykinin is released from H-kininogen on the surface of CHO-745 cells only by serine proteases; however, in CHO-K1 cells either serine or cysteine proteases are found to be involved. The CHO-K1 cell lysate contains different kininogenases. Plasma prekallikrein endocytosis in CHO-K1 cells is independent of H-kininogen, and also prekallikrein is not internalized by CHO-745 cells. Plasma prekallikrein cleavage/activation is independent of glycosaminoglycans but plasma kallikrein formation is more specific on H-kininogen assembled on the cell surface through glycosaminoglycans. In this mini-review, the importance of HSPGs in the regulation of plasma kallikrein-kinin system proteins is shown.
... As vascular agents they promote vascular permeability and vasodilatation (Leeb-Lundberg et al.), which are important mechanisms related to the anti-hypertensive action of kinase II inhibitors (Lindsey et al., 1987). In particular, bradykinin and kallidin are powerful algesic and vasoactive peptides generated locally following the proteolytic cleavage of their precursors, high-and low-molecular-weight cultures and in various regions of the brain including the medulla oblongata, the pons, the cerebral cortex and the hippocampus (Damasceno et al., 2015). ...
Kinins are vasoactive peptides that promote pain and inflammation, yet centrally believed to participate to cardiovascular defensive reflexes produced by noxious stimuli. These peptides signal through the activation of two transmembrane G-protein-coupled receptors named B1 and B2 receptors (B1R and B2R). The B2R is constitutive in healthy tissues and animals. The aim of the study was to measure the gene and protein expression of B2R kinin receptors in central and peripheral tissues isolated from control rats and rats were pre-treated with capsaicin on the second day of life (50 mg/kg, s.c.) or two weeks prior to sacrifice (125 mg/kg over three days, s.c.). The same treatment with saline was made in control animals. Levels of mRNA for B2R were measured by quantitative RT-PCR and Qualitative while receptor binding sites were measured on tissue sections with the radioligands¹²⁵I-HPP-Hoe 140 (B2R). B2R was expressed in all studied tissues (hypothalamus, paratrigeminal nucleus, nucleus of solitary tract, spinal cord, aorta and liver) and treatment capsaicin neonates when compared to controls, did not affect its level of expression. Capsaicin had no significant effect on the expression of B2R in some tissues on binding sites. The synthesis of B2R kinin receptor is not associated with sensory C-fibre and tissues showed no significant difference indicating that B2R was regulated by distinct mechanisms.
