-
IBRO Neuroscience Reports Jun 2024Biomarkers are measured to evaluate physiological and pathological processes as well as responses to a therapeutic intervention. Biomarkers can be classified as... (Review)
Review
Biomarkers are measured to evaluate physiological and pathological processes as well as responses to a therapeutic intervention. Biomarkers can be classified as diagnostic, prognostic, predictor, clinical, and therapeutic. In Alzheimer's disease (AD), multiple biomarkers have been reported so far. Nevertheless, finding a specific biomarker in AD remains a major challenge. Three databases, including PubMed, Web of Science, and Scopus were selected with the keywords of Alzheimer's disease, neuroimaging, biomarker, and blood. The results were finalized with 49 potential CSF/blood and 35 neuroimaging biomarkers. To distinguish normal from AD patients, amyloid-beta (Aβ), plasma glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) as potential biomarkers in cerebrospinal fluid (CSF) as well as the serum could be detected. Nevertheless, most of the biomarkers fairly change in the CSF during AD, listed as kallikrein 6, virus-like particles (VLP-1), galectin-3 (Gal-3), and synaptotagmin-1 (Syt-1). From the neuroimaging aspect, atrophy is an accepted biomarker for the neuropathologic progression of AD. In addition, Magnetic resonance spectroscopy (MRS), diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), tractography (DTT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI), can be used to detect AD. Using neuroimaging and CSF/blood biomarkers, in combination with artificial intelligence, it is possible to obtain information on prognosis and follow-up on the different stages of AD. Hence physicians could select the suitable therapy to attenuate disease symptoms and follow up on the efficiency of the prescribed drug.
PubMed: 38497046
DOI: 10.1016/j.ibneur.2024.02.007 -
The Journal of Allergy and Clinical... Nov 2023Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and...
BACKGROUND
Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and clinical heterogenicity. Most cases are caused by genetic variants in the SERPING1 gene leading to plasma deficiency of the encoded protein C1 inhibitor (C1INH). More than 500 different hereditary angioedema-causing variants have been identified in the SERPING1 gene, but the disease mechanisms by which they result in pathologically low C1INH plasma levels remain largely unknown.
OBJECTIVES
The aim was to describe trans-inhibitory effects of full-length or near full-length C1INH encoded by 28 disease-associated SERPING1 variants.
METHODS
HeLa cells were transfected with expression constructs encoding the studied SERPING1 variants. Extensive and comparative studies of C1INH expression, secretion, functionality, and intracellular localization were carried out.
RESULTS
Our findings characterized functional properties of a subset of SERPING1 variants allowing the examined variants to be subdivided into 5 different clusters, each containing variants sharing specific molecular characteristics. For all variants except 2, we found that coexpression of mutant and normal C1INH negatively affected the overall capacity to target proteases. Strikingly, for a subset of variants, intracellular formation of C1INH foci was detectable only in heterozygous configurations enabling simultaneous expression of normal and mutant C1INH.
CONCLUSIONS
We provide a functional classification of SERPING1 gene variants suggesting that different SERPING1 variants drive the pathogenicity through different and in some cases overlapping molecular disease mechanisms. For a subset of gene variants, our data define some types of hereditary angioedema with C1INH deficiency as serpinopathies driven by dominant-negative disease mechanisms.
Topics: Humans; Complement C1 Inhibitor Protein; Angioedemas, Hereditary; HeLa Cells; Endopeptidases; Peptide Hydrolases
PubMed: 37301409
DOI: 10.1016/j.jaci.2023.04.023 -
Journal of Translational Medicine Apr 2024The kallikrein-kinin system is a key regulatory cascade involved in blood pressure maintenance, hemostasis, inflammation and renal function. Currently, approved drugs... (Review)
Review
BACKGROUND
The kallikrein-kinin system is a key regulatory cascade involved in blood pressure maintenance, hemostasis, inflammation and renal function. Currently, approved drugs remain limited to the rare disease hereditary angioedema. However, growing interest in this system is indicated by an increasing number of promising drug candidates for further indications.
METHODS
To provide an overview of current drug development, a two-stage literature search was conducted between March and December 2023 to identify drug candidates with targets in the kallikrein-kinin system. First, drug candidates were identified using PubMed and Clinicaltrials.gov. Second, the latest publications/results for these compounds were searched in PubMed, Clinicaltrials.gov and Google Scholar. The findings were categorized by target, stage of development, and intended indication.
RESULTS
The search identified 68 drugs, of which 10 are approved, 25 are in clinical development, and 33 in preclinical development. The three most studied indications included diabetic retinopathy, thromboprophylaxis and hereditary angioedema. The latter is still an indication for most of the drug candidates close to regulatory approval (3 out of 4). For the emerging indications, promising new drug candidates in clinical development are ixodes ricinus-contact phase inhibitor for thromboprophylaxis and RZ402 and THR-149 for the treatment of diabetic macular edema (all phase 2).
CONCLUSION
The therapeutic impact of targeting the kallikrein-kinin system is no longer limited to the treatment of hereditary angioedema. Ongoing research on other diseases demonstrates the potential of therapeutic interventions targeting the kallikrein-kinin system and will provide further treatment options for patients in the future.
Topics: Humans; Kallikrein-Kinin System; Drug Discovery; Drug Development; Animals
PubMed: 38671481
DOI: 10.1186/s12967-024-05216-5 -
Biochemical and Biophysical Research... Dec 2023The incidence and mortality rates of colorectal cancer (CRC) have significantly increased in recent years. It has been shown that early diagnosis of CRC improves the...
The incidence and mortality rates of colorectal cancer (CRC) have significantly increased in recent years. It has been shown that early diagnosis of CRC improves the five-year survival of patients compared to late diagnosis, as patients with stage I disease have a five-year survival rate as high as 90 %. Through bioinformatics analysis, we identified Kallikrein 10 (KLK10), a member of the Kallikrein family, as a reliable predictor of CRC progression, particularly in patients with early-stage CRC. Furthermore, single-cell analysis revealed that KLK10 was highly expressed in tumor and partial immune cells. Analysis of the biological functions of KLK10 using the Kyoto encyclopedia of genes and genomes and gene ontology indicated that KLK10 plays a role in the proliferation and differentiation of cancer cells, along with the maintenance of tumor function and immune regulation, explicitly by T cells and macrophages. EdU cell proliferation staining, plate clone formation assay, and cell scratch assay demonstrated that KLK10 inhibition by siRNA affected the proliferation and migration of CRC cells. Cell cycle detection by flow cytometry demonstrated that KLK10 inhibition led to cell cycle arrest in the G1 phase. In addition, the proportion of M1 and M2 macrophages in 45 tumor specimens was analyzed by immunohistochemistry, the proportion of CD4 T cells and CD8 T cells in plasma was identified by flow cytometry, and their correlation with KLK10 was analyzed. The effects of KLK10 on T cells and macrophages were verified in independent cell experiments. The results revealed that KLK10 also activates CD4 T cells, mediating M2-type macrophage polarization.
Topics: Humans; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Kallikreins
PubMed: 37972446
DOI: 10.1016/j.bbrc.2023.149217 -
Frontiers in Medicine 2023SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and... (Review)
Review
SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and obesity-conditions linked by the presence of endothelial pathology. Viral infection in this setting causes increased conversion of circulating Factor XII to its active form (FXIIa). This is the first step in the contact-kinin pathway, leading to synchronous activation of the intrinsic coagulation cascade and the plasma Kallikrein-Kinin system, resulting in clotting and inflammatory lung disease. Temporal trends are evident from blood results of hospitalized patients. In the first week of symptoms the activated partial thromboplastin time (APTT) is prolonged. This can occur when clotting factors are consumed as part of the contact (intrinsic) pathway. Platelet counts initially fall, reflecting their consumption in coagulation. Lymphopenia occurs after approximately 1 week, reflecting the emergence of a lymphocytic pneumonitis [COVID-19 acute respiratory distress syndrome (ARDS)]. Intrinsic coagulation also induces the contact-kinin pathway of inflammation. A major product of this pathway, bradykinin causes oedema with ground glass opacities (GGO) on imaging in early COVID-19. Bradykinin also causes release of the pleiotrophic cytokine IL-6, which causes lymphocyte recruitment. Thromobosis and lymphocytic pneumonitis are hallmark features of COVID-19 ARDS. In this review we examine the literature with particular reference to the contact-kinin pathway. Measurements of platelets, lymphocytes and APTT should be undertaken in severe infections to stratify for risk of developing ARDS.
PubMed: 37448794
DOI: 10.3389/fmed.2023.1208866 -
Carbohydrate Polymers Nov 2023Pentosan polysulfate sodium (PPS) is a semi-synthetic, heparin-like polysaccharide with manifold therapeutic actions. It is approved for treatment of bladder pain...
Pentosan polysulfate sodium (PPS) is a semi-synthetic, heparin-like polysaccharide with manifold therapeutic actions. It is approved for treatment of bladder pain syndrome / interstitial cystitis in humans and treatment of musculoskeletal diseases in animals. PPS is produced by a complex procedure using beech wood as starting material. It consists of a mixture of sulfated glucuronoxylans, whose structural composition cannot be fully characterized by physicochemical analysis. The question arises whether PPS follow-on products are identical with the original and thus meet the requirement for generic drug application. The aim of this study was to investigate whether commercially available PPS products differ in physicochemical characteristics and biological effects from the original. Ten PPS preparations from different manufactures were analyzed using orthogonal analytical techniques including, inter alia, size exclusion chromatography with triple detection, nuclear magnetic resonance spectroscopy, and high-resolution mid-infrared spectroscopy in aqueous solution with chemometric evaluation. For functional analysis, we measured the plasma kallikrein generation in human plasma and FXII activation. The study revealed significant structural and biological differences between PPS from different sources. Therefore, follow-on products cannot be considered identical but at best similar to original PPS. However, their similar efficacy and safety have still to be proven by comprehensive studies.
PubMed: 37567725
DOI: 10.1016/j.carbpol.2023.121201 -
Frontiers in Immunology 2023Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation.
METHODS
We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively.
RESULTS
The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms ( = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms ( = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug.
CONCLUSION
The study results do not support the use of ConA to prevent COVID-19 progression.
CLINICAL TRIAL REGISTRATION
https://clinicaltrials.gov, identifier NCT04414631.
Topics: Adult; Humans; COVID-19; SARS-CoV-2; Endothelial Cells; Inflammation; Thrombosis
PubMed: 37965347
DOI: 10.3389/fimmu.2023.1255292 -
The Journal of Allergy and Clinical... May 2024Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1...
BACKGROUND
Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 inhibitor (HAE-nC1-INH) is an underdiagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood.
OBJECTIVE
We sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency.
METHODS
This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients' clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and ClinPred) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing.
RESULTS
Patients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity-30% to 50% of median value in plasma. We identified 3 variants of the gene encoding the catalytic 55-kDa subunit of CPN: c.533G>A, c.582A>G, and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members.
CONCLUSIONS
gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms.
PubMed: 38445235
DOI: 10.1016/j.jacig.2024.100223 -
Frontiers in Immunology 2024Hereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased...
BACKGROUND
Hereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022.
METHODS
We conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy.
RESULTS
From June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p<0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3.
CONCLUSION
Berotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.
Topics: Humans; Angioedemas, Hereditary; Quality of Life; Retrospective Studies; Canada; Angioedema; Pyrazoles
PubMed: 38318176
DOI: 10.3389/fimmu.2024.1339421 -
Journal of Thrombosis and Haemostasis :... Aug 2023Patients with liver diseases are in a hypercoagulable state, as evidenced by enhanced in vitro thrombin generating capacity and elevated plasma levels of markers of...
BACKGROUND
Patients with liver diseases are in a hypercoagulable state, as evidenced by enhanced in vitro thrombin generating capacity and elevated plasma levels of markers of in vivo thrombin generation. However, it is unknown by which mechanism in vivo activation of coagulation occurs.
OBJECTIVES
We aimed to clarify the mechanisms underlying enhanced in vivo thrombin generation to provide a rationale for targeted anticoagulant therapy.
PATIENTS/METHODS
Overall, 191 patients diagnosed with stable or acutely decompensated cirrhosis, acute liver failure or injury, acute-on-chronic liver failure, or sepsis without underlying chronic liver disease were recruited from King's College Hospital, London, from 2017 to 2021 and compared with reference values of 41 healthy controls. We measured levels of markers of in vivo activation of coagulation and activation of the intrinsic and extrinsic pathways, their respective zymogens, and natural anticoagulants.
RESULTS
Thrombin-antithrombin complexes, prothrombin fragment 1+2 (F1+2), and D-dimer levels were increased in acute and chronic liver disease, proportional to disease severity. Plasma levels of free activated factor XII (FXIIa), C1-esterase-inhibitor (C1inh)-FXIIa, C1inh-factor XI, C1inh-plasma kallikrein, factor-VIIa-antithrombin-complexes, and activated FVII were reduced in acute and chronic liver disease, even after adjusting for zymogen levels, which were also substantially reduced. Natural anticoagulants antithrombin and protein C were profoundly reduced in liver patients.
CONCLUSIONS
This study provides evidence of enhanced thrombin generation in liver disease without detectable activation of the intrinsic or extrinsic pathway. We propose that defective anticoagulant mechanisms highly amplify the low-grade activation of coagulation by either pathway.
Topics: Humans; Thrombin; Blood Coagulation; Anticoagulants; Liver Diseases; Antithrombins
PubMed: 36990155
DOI: 10.1016/j.jtha.2023.03.017