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ACS Medicinal Chemistry Letters Aug 2022
PubMed: 35978687
DOI: 10.1021/acsmedchemlett.2c00323 -
ACS Medicinal Chemistry Letters Apr 2022
PubMed: 35450363
DOI: 10.1021/acsmedchemlett.2c00085 -
ACS Medicinal Chemistry Letters Jun 2022
PubMed: 35707157
DOI: 10.1021/acsmedchemlett.2c00193 -
Frontiers in Cardiovascular Medicine 2022The contact system consists of coagulation factor XII (FXII), prekallikrein, and H-kininogen (HK) and plays important roles in many diseases. Plasma kallikrein (PKa)...
OBJECTIVES
The contact system consists of coagulation factor XII (FXII), prekallikrein, and H-kininogen (HK) and plays important roles in many diseases. Plasma kallikrein (PKa) cleaved HK (cHK) is a marker of contact activation. Presently, we developed a specific and precise enzyme-linked immunosorbent assay (ELISA) for determination of cHK and
METHODS
Cleaved HK specific mouse monoclonal antibodies (mAbs) were generated using a peptide corresponding to the PKa cleavage site on HK as immunogen. ELISA, surface plasmon resonance analysis, and immunoprecipitation established the specificity of the antibody, which subsequently was used in a sandwich ELISA. The analytical imprecision and the concentration of cHK in a reference population and in women receiving oral contraceptives (OC) were determined. cHK was assessed in plasma exposed to polytetrafluoroethylene, silicone, and glass tubes.
RESULTS
The selected mAb showed excellent specificity towards cHK. The intra-assay and inter-assay CV of the ELISA were 3.6 and 6.0%, respectively. The reference population (60 women, 60 men) displayed a median cHK plasma concentration of 1.38 μg/mL and a reference interval of 0.82 - 2.56 μg/mL. Women receiving OC had significantly higher concentrations, < 0.001. cHK was significantly elevated in plasma exposed to polytetrafluoroethylene, = 0.001, and glass, < 0.0001.
CONCLUSION
The ELISA showed excellent precision and specificity. cHK assessment demonstrated ongoing contact activation in healthy individuals, augmented by OC. The cHK antibody and the ELISA could be promising tools in contact activation related diseases and investigations of the plasma compatibility of blood contacting biomaterials.
PubMed: 35669477
DOI: 10.3389/fcvm.2022.873975 -
Biomarker Research May 2023Blood tests would be much easier to implement in the clinical diagnosis of Alzheimer's disease (AD) as minimally invasive measurements. Multiple inspection technologies...
BACKGROUND
Blood tests would be much easier to implement in the clinical diagnosis of Alzheimer's disease (AD) as minimally invasive measurements. Multiple inspection technologies promoted AD-associated blood biomarkers' exploration. However, there was a lack of further screening and validation for these explored blood-based biomarkers. We selected four potential biomarkers to explore their plasma levels in AD and amnestic mild cognitive impairment (aMCI) and developed a composite panel for AD and aMCI screening.
METHOD
The plasma concentrations of soluble low-density lipoprotein receptor-associated protein 1 (sLRP1), Gelsolin (GSN), Kallikrein 4 (KLK4) and Caspase 3 were measured in the discovery and validation cohort. The receiver operating characteristic (ROC) curve was generated to assess the classification panel with the area under the curve (AUC).
RESULTS
A total of 233 participants (26 CN, 27 aMCI, and 26 AD in the discovery cohort, and 51 CN, 50 aMCI, and 53 AD in the validation cohort) with complete data were included in the study. The plasma concentrations of sLRP1 and Caspase 3 were significantly decreased in AD and aMCI when compared with those in the CN group. Compared with the CN group, the concentrations of KLK4 and GSN were increased in AD, but not in MCI. Interestingly, one of four proteins, sLRP1 in plasma level was higher in Apolipoprotein E (APOE) ε4 non-carriers than that in APOE ε4 carriers, especially among CN and MCI. No significant difference was found between females and males in the plasma levels of four proteins. The composite panel is based on four blood biomarkers accurately classifying AD from CN (AUC = 0.903-0.928), and MCI from CN (AUC = 0.846-0.865). Moreover, dynamic changes in the plasma levels of four proteins exhibited a significant correlation with cognitive assessment.
CONCLUSIONS
Altogether, these findings indicate that the plasma levels of sLRP1, KLK4, GSN and Caspase 3 changed with the progression of AD. And their combination could be used to develop a panel for classifying AD and aMCI with high accuracy, which would provide an alternative approach for developing a blood-based test for AD and aMCI screening.
PubMed: 37194047
DOI: 10.1186/s40364-023-00485-6 -
Mediators of Inflammation 2022The COVID-19 pandemic is rapidly spreading, and health care systems are being overwhelmed with the huge number of cases, with a good number of cases requiring intensive... (Review)
Review
The COVID-19 pandemic is rapidly spreading, and health care systems are being overwhelmed with the huge number of cases, with a good number of cases requiring intensive care. It has become imperative to develop safe and effective treatment strategies to improve survival. In this regard, understanding the pathogenesis of COVID-19 is highly important. Many hypotheses have been proposed, including the ACE/angiotensin-II/angiotensin receptor 1 pathway, the complement pathway, and the angiotensin-converting enzyme 2/mitochondrial assembly receptor (ACE2/MasR) pathway. SARS-CoV-2 binds to the ACE2 on the cell surface, downregulating the ACE2, and thus impairs the inactivation of bradykinin and des-Arg9-bradykinin. Bradykinin, a linear nonapeptide, is extensively distributed in plasma and different tissues. Kininogens in plasma and tissue are the main sources of the two vasoactive peptides called bradykinin and kallidin. However, the role of the dysregulated bradykinin pathway is less explored in the pathogenesis of COVID-19. Understanding the pathogenesis of COVID-19 is crucial for the development of new effective treatment approaches which interfere with these pathways. In this review, we have tried to explore the interaction between SARS-CoV-2, ACE2, bradykinin, and its metabolite des-Arg9-bradykinin in the pathogenesis of COVID-19.
Topics: Angiotensin-Converting Enzyme 2; Bradykinin; COVID-19; Humans; Kallikrein-Kinin System; Receptors, Bradykinin; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35153624
DOI: 10.1155/2022/7423537 -
Seminars in Ophthalmology 2016Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of... (Review)
Review
Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein-kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention.
Topics: Animals; Capillary Permeability; Diabetic Retinopathy; Humans; Kallikrein-Kinin System; Macular Edema; Plasma Kallikrein; Retinal Vessels; Vascular Endothelial Growth Factor A
PubMed: 26959125
DOI: 10.3109/08820538.2015.1114829 -
Frontiers in Immunology 2017Anaphylaxis is a life-threatening allergic reaction. It is triggered by the release of pro-inflammatory cytokines and mediators from mast cells and basophils in response... (Review)
Review
Anaphylaxis is a life-threatening allergic reaction. It is triggered by the release of pro-inflammatory cytokines and mediators from mast cells and basophils in response to immunologic or non-immunologic mechanisms. Mediators that are released upon mast cell activation include the highly sulfated polysaccharide and inorganic polymer heparin and polyphosphate (polyP), respectively. Heparin and polyP supply a negative surface for factor XII (FXII) activation, a serine protease that drives contact system-mediated coagulation and inflammation. Activation of the FXII substrate plasma kallikrein leads to further activation of zymogen FXII and triggers the pro-inflammatory kallikrein-kinin system that results in the release of the mediator bradykinin (BK). The severity of anaphylaxis is correlated with the intensity of contact system activation, the magnitude of mast cell activation, and BK formation. The main inhibitor of the complement system, C1 esterase inhibitor, potently interferes with FXII activity, indicating a meaningful cross-link between complement and kallikrein-kinin systems. Deficiency in a functional C1 esterase inhibitor leads to a severe swelling disorder called hereditary angioedema (HAE). The significance of FXII in these disorders highlights the importance of studying how these processes are integrated and can be therapeutically targeted. In this review, we focus on how FXII integrates with inflammation and the complement system to cause anaphylaxis and HAE as well as highlight current diagnosis and treatments of BK-related diseases.
PubMed: 28966616
DOI: 10.3389/fimmu.2017.01115 -
Journal of Innate Immunity 2018The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin,...
The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin, the coagulation, and the fibrinolytic systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by the C3 convertase. Also, kallikrein-generated C3b forms C3 convertases, which trigger the C3 amplification loop. Since kallikrein also cleaves factor B to yield Bb and Ba, kallikrein alone can trigger complement activation. Kallikrein-generated C3 convertases are inhibited by factor H; thus, the kallikrein activation pathway merges with the amplification loop of the alternative pathway. Taken together, these data suggest that activation of the contact system locally enhances complement activation on cell surfaces. The human pathogenic microbe Candida albicans activates the contact system in normal human serum. However, C. albicans immediately recruits factor H to the surface, thereby evading the alternative and likely kallikrein-mediated complement pathways.
Topics: Amino Acid Sequence; Animals; Candida albicans; Candidiasis; Cell Line, Transformed; Complement Activation; Complement C3; Complement C3-C5 Convertases; Complement C3b; Complement Factor B; Complement Factor D; Complement Factor H; Complement Pathway, Alternative; Factor XII; Female; Humans; Immune Evasion; Kallikreins; Mice, Inbred BALB C; Protein Binding
PubMed: 29237166
DOI: 10.1159/000484257 -
Allergologie Select 2018The aim of treatment of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (HAE-C1-INH) is either treating acute attacks or preventing attacks by using... (Review)
Review
The aim of treatment of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (HAE-C1-INH) is either treating acute attacks or preventing attacks by using prophylactic treatment. For treating acute attacks, plasma-derived C1 inhibitor (C1-INH) concentrates, a bradykinin B2 receptor antagonist, and a recombinant human C1-INH are available in Europe. In the United States, a plasma-derived C1-INH concentrate, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor were approved for the treatment of acute attacks. Fresh frozen plasma is also available for treating acute attacks. Short-term prophylactic treatment focuses on C1-INH and attenuated androgens. Long-term prophylactic treatments include attenuated androgens such as danazol, stanozolol, and oxandrolone, antifibrinolytics, and a plasma-derived C1-INH concentrate. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are admitted for self-administration and home therapy. So the number of management options increased considerably within the last few years thus helping to diminish the burden of HAE.
PubMed: 31826031
DOI: 10.5414/ALX1561E