Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 88
Filter
1.
Cytokine ; 157: 155974, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1956119

ABSTRACT

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) have increased risk for acute kidney injury (AKI). The exacerbation of the immune response seems to contribute to AKI development, but the immunopathological process is not completely understood. OBJECTIVES: To analyze levels of circulant immune mediators in COVID-19 patients evolving with or without AKI. We have also investigated possible associations of these mediators with viral load and clinical outcomes. METHODS: This is a longitudinal study performed with hospitalized patients with moderate to severe COVID-19. Serum levels of 27 immune mediators were measured by a multiplex immunoassay. Data were analyzed at two timepoints during the follow-up: within the first 13 days of the disease onset (early sample) and from the 14th day to death or hospital discharge (follow-up sample). RESULTS: We studied 82 COVID-19 patients (59.5 ± 17.5 years, 54.9% male). Of these, 34 (41.5%) developed AKI. These patients presented higher SARS-CoV-2 viral load (P = 0.03), higher frequency of diabetes (P = 0.01) and death (P = 0.0004). Overall, AKI patients presented significantly higher and sustained levels (P < 0.05) of CCL-2, CCL-3, CCL-4, CXCL-8, CXCL-10, IFN-γ, IL-2, IL-6, TNF-α, IL-1Ra, IL-10 and VEGF. Importantly, higher levels of CCL-2, CXCL-10, IL-2, TNF-α, IL-10, FGFb, and VEGF were observed in AKI patients independently of death. ROC curves demonstrated that early alterations in CCL-2, CXCL-8, CXCL-10, IFN-γ, IL-6, IL-1Ra and IL-10 show a good predictive value regarding AKI development. Lastly, immune mediators were significantly associated with each other and with SARS-CoV-2 viral load in AKI patients. CONCLUSIONS: COVID-19 associated AKI is accompanied by substantial alterations in circulant levels of immune mediators, which could significantly contribute to the establishment of kidney injury.


Subject(s)
Acute Kidney Injury , COVID-19 , Acute Kidney Injury/pathology , COVID-19/complications , Female , Humans , Immunologic Factors , Interleukin 1 Receptor Antagonist Protein , Interleukin-10 , Interleukin-2 , Interleukin-6 , Longitudinal Studies , Male , Retrospective Studies , Risk Factors , SARS-CoV-2 , Tumor Necrosis Factor-alpha , Vascular Endothelial Growth Factor A
2.
Tuberk Toraks ; 70(2): 179-186, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1934519

ABSTRACT

Introduction: Although the epidemiological and clinical characteristics of COVID-19 patients have been described; the pathogenesis of the disease and its long-term consequences are still unclear. Pulmonary fibrosis is one of these late outcomes. In this study we evaluated Interleukin-17 (IL-17), vascular endothelial growth factor (VEGF), and immunoglobulin G4 (IgG4) levels of COVID-19 infected patients with different clinical course and their effect on pulmonary fibrosis in post-COVID period. Materials and Methods: In total, 90 patients were evaluated. Among the patients who presented for a control visit between 3-12 weeks after acute infection; patients with signs of pulmonary sequelae radiologically (traction bronchiectasis, interseptal thickening, disorders in parenchyma architecture) were classified as Group I (n= 32), patients who recovered without sequelae radiologically as Group II (n= 32). The Control group included healthy individuals who did not have COVID-19, and was classified as Group III (n= 26). Result: The mean age in Group I was significantly higher than Group II and III (p<0.001). There was a statistically significant difference between the VEGF and IL-17 values based on the patient group they are in (p<0.05). Vascular endothelial growth factor values of Group I and III were significantly lower than the patients in Group II (p<0.001). IL-17 values of Group I and II were found to be significantly lower than Group III (p= 0.005). There was no statistically significant relationship between groups in terms of IgG4 values. Conclusions: In our study, it was observed that the profibrotic effects of VEGF, IL-17, and IgG4 were not dominant in patients who recovered with pulmonary sequelae after COVID; therefore, it is thought that different mechanisms mentioned or not yet revealed may cause this outcome.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Disease Progression , Humans , Immunoglobulin G , Interleukin-17 , Lung/diagnostic imaging , Pulmonary Fibrosis/etiology , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
3.
Int J Mol Sci ; 23(13)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1934134

ABSTRACT

Chia seed peptides (CSP) can be a source of multifunctional biopeptides to treat non-communicable diseases. However, interactions and binding affinity involved in targeting specific receptors remains unexplored. In this study, molecular simulation techniques were used as virtual screening of CSP to determine drug-like candidates using a multi-target-directed ligand approach. CSP fraction with the best bioactivities in vitro was sequenced. Then, a prediction model was built using physicochemical descriptors (hydrophobicity, hydrophilicity, intestinal stability, antiangiogenic, antihypertensive, and anti-inflammatory) to calculate potential scores and rank possible biopeptides. Furthermore, molecular dynamics simulations (MDS) and ensemble molecular docking analysis were carried out using four human protein targets (ACE, angiotensin converting enzyme; VEGF, vascular endothelial growth factor; GLUC, glucocorticoid and MINC, mineralocorticoid receptors). Five known-sequence peptides (NNVFYPF, FNIVFPG, SRPWPIDY, QLQRWFR, GSRFDWTR) and five de novo peptides (DFKF, DLRF, FKAF, FRSF, QFRF) had the lowest energy score and higher affinity for ACE and VEGF. The therapeutic effects of these selected peptides can be related to the inhibition of the enzymes involved in angiogenesis and hypertension, due to formation of stable complexes with VEGF and ACE binding sites, respectively. The application of MDS is a good resource for identifying bioactive peptides for future experimental validation.


Subject(s)
Salvia hispanica , Salvia , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptides/chemistry , Plant Extracts , Salvia/chemistry , Vascular Endothelial Growth Factor A
4.
BMC Ophthalmol ; 22(1): 228, 2022 May 20.
Article in English | MEDLINE | ID: covidwho-1902365

ABSTRACT

BACKGROUND: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic in 2020 outpatient care of neovascular age-related macular degeneration (nAMD) patients was severely reduced due to lockdown. Missed visits are known to be detrimental to patients in need of continued anti-vascular endothelial growth factor (VEGF) intravitreal injections (IVIs). The purpose of the study was to assess the effect of a month-long pause of regular visits and anti-VEGF IVIs in nAMD patients. METHODS: A retrospective study was performed. Patients were treated in a pro re nata ("as needed") scheme. Distance (logMAR) and near (logRAD) visual acuity (VA), optical coherence tomography, delay between planned and actual visit date and the indication for IVI were assessed for 3 continous visits in the 6 months before lockdown (V-3, -2, -1) and the 2 visits after lockdown (V0, V + 1). For analysis of long-term impact, records for visits 1 years before and after lockdown (V-3, V + 2) were gathered. RESULTS: We included 166 patients (120 female, 46 male) with a median (range) age of 80.88 (59.8-99.36) years. Compared to V-1, distance VA was significantly worse at both V0 (0.27 ± 0.21 vs 0.31 ± 0.23 logMAR, p < 0.001) and V + 1 (0.27 ± 0.21 vs 0.30 ± 0.23 logMAR, p = 0.021). Near VA was significantly worse at both V0 (0.31 ± 0.21 vs 0.34 ± 0.22 logRAD, p = 0.037) and V + 1 (0.31 ± 0.21 vs 0.34 ± 0.22 logRAD, p = 0.02). Visit delay (VD) at V0 was significantly longer than at V + 1 (30.81 ± 20.44 vs 2.02 ± 6.79 days, p < 0.0001). Linear regression analysis showed a significant association between visit delay and a reduction of near VA between V-1 and V + 1 (p = 0.0223). There was a significant loss of distance VA (p = 0.02) in the year after the lockdown period (n = 125) compared to the year before. Loss of reading acuity was not significantly increased (p = 0.3). One year post lockdown, there was no correlation between VA change and visit delay after lockdown (p > 0.05). CONCLUSIONS: In nAMD patients whose visits and treatment were paused for a month during the first wave of the COVID-19 pandemic, we found a loss of VA immediately after lockdown, which persisted during follow-up despite re-established anti-VEGF treatment. In the short term, length of delay was predictive for loss of reading VA. The comparison of development of VA during the year before and after the lockdown showed a progression of nAMD related VA loss which may have been accelerated by the disruption of regular visits and treatment. TRIAL REGISTRATION: This article does not report the outcome of a health care intervention. This retrospective study was therefore not registered in a clinical trials database.


Subject(s)
COVID-19 , Macular Degeneration , Wet Macular Degeneration , Aged, 80 and over , Angiogenesis Inhibitors/therapeutic use , COVID-19/epidemiology , Communicable Disease Control , Female , Follow-Up Studies , Humans , Intravitreal Injections , Macular Degeneration/drug therapy , Male , Pandemics , Ranibizumab/therapeutic use , Retrospective Studies , Vascular Endothelial Growth Factor A , Wet Macular Degeneration/drug therapy , Wet Macular Degeneration/epidemiology
5.
BMJ Open ; 12(6): e058266, 2022 06 15.
Article in English | MEDLINE | ID: covidwho-1902003

ABSTRACT

OBJECTIVES: In order to better understand the continued barriers to the provision of vascular endothelial inhibitor therapy, this study aims to investigate patients' experiences with neovascular age-related macular degeneration (nvAMD) in Germany during the injection process and how they deal with it. DESIGN AND PARTICIPANTS: This analysis is part of the qualitative arm of a wider mixed-methods study. We recruited participants all over Germany via ophthalmologists, eye clinics, general practitioners, care bases and support groups between June 2018 and December 2020 and selected a subsample of study participants with nvAMD who were either undergoing or had previously undergone vascular endothelial growth factor inhibitor therapy. We conducted narrative, semistructured, face-to-face interviews at the participants' homes, which were audio-recorded. The interviews were thematically analysed. RESULTS: Twenty-two participants were included in this analysis. Experiencing neovascular macular degeneration was dominated by the injection experience. Study participants perceived the treatment with vascular endothelial inhibitor injections as uncomfortable, and they described undergoing varying levels of anxiety during the whole injection process. After some years of receiving multiple injections, the pain and not experiencing any positive effects made participants with significant vision loss want to discontinue therapy. Furthermore, they narrated negative injection experiences in association with their interactions with medical staff and doctors. CONCLUSION: Although time in the medical setting is limited, efficient and good doctor-patient relationships seem crucial for satisfying care experiences. A respectful and humane relationship may be one key to achieving treatment adherence.


Subject(s)
Intravitreal Injections , Macular Degeneration , Wet Macular Degeneration , Angiogenesis Inhibitors/therapeutic use , Germany , Humans , Intravitreal Injections/psychology , Macular Degeneration/drug therapy , Macular Degeneration/psychology , Qualitative Research , Ranibizumab , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/therapeutic use , Wet Macular Degeneration/drug therapy , Wet Macular Degeneration/psychology
6.
Life Sci ; 304: 120703, 2022 Sep 01.
Article in English | MEDLINE | ID: covidwho-1885980

ABSTRACT

AIMS: Biologically active molecules cytokines and growth factors (GFs) are critical regulators of tissue injury/repair and emerge as key players in COVID-19 pathophysiology. However, specific disease stage of GFs dysregulation and, whether these GFs have associations with thromboembolism and tissue injury/repair in COVID-19 remain vague. MAIN METHODS: GF profiling in hospitalized moderate (non-ICU) and critically ill (ICU) COVID-19 patients was performed through legendPlex assay. KEY FINDINGS: Investigation revealed profound elevation of VEGF, PDGFs, EGF, TGF-α, FGF-basic, and erythropoietin (EPO) in moderate cases and decline or trend of decline with disease advancement. We found strong positive correlations of plasma VEGF, PDGFs, and EPO with endothelial dysfunction markers P-selectin and sCD40L. Interestingly, the HGF and G-CSF were upregulated at the moderate stage and remained elevated at the severe stage of COVID-19. Moreover, strong negative correlations of PDGFs (r2 = 0.238, P = 0.006), EPO (r2 = 0.18, P = 0.01) and EGF (r2 = 0.172, P = 0.02) and positive correlation of angiopoietin-2 (r2 = 0.267, P = 0.003) with D-dimer, a marker of thromboembolism, was observed. Further, plasma PDGFs (r2 = 0.199, P = 0.01), EPO (r2 = 0.115, P = 0.02), and EGF (r2 = 0.108, P = 0.07) exhibited negative correlations with tissue injury marker, myoglobin. SIGNIFICANCE: Taken together, unlike cytokines, most of the assessed GFs were upregulated at the moderate stage of COVID-19. The induction of GFs likely occurs due to endothelial dysfunction and may counter the adverse effects of cytokine storms which is reflected by inverse correlations of PDGFs, EPO, and EGF with thromboembolism and tissue injury markers. The findings suggest that the assessed GFs play differential roles in the pathogenesis of COVID-19.


Subject(s)
COVID-19 , Thromboembolism , Biomarkers , Cytokines , Epidermal Growth Factor , Humans , Platelet-Derived Growth Factor , Receptors, Erythropoietin , SARS-CoV-2 , Vascular Endothelial Growth Factor A
7.
J Med Microbiol ; 71(5)2022 May.
Article in English | MEDLINE | ID: covidwho-1874076

ABSTRACT

Introduction. Coronavirus disease 2019 (COVID-19) has caused a serious threat to public health worldwide, and there is currently no effective therapeutic strategy for treating COVID-19.Hypothesis/Gap Statement. We propose that sophocarpine (SOP) might have potential therapeutic effects on COVID-19 through inhibiting the cytokine storm and the nuclear factor NF-κB signalling pathway.Aim. The objective was to elucidate the potential mechanism of SOP against COVID-19 through a network pharmacology analysis and its experimental validation.Methodology. The BATMAN-TCM database was used to identify the therapeutic targets of SOP, while the GeneCards and DisGeNET databases were used to identify the targets related to COVID-19. A protein-protein interaction (PPI) network was constructed from the STRING and analysed using Cytoscape software. Gene ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and disease ontology (DO) enrichment analyses of the co-targets were performed using Metascape. Autodock 4.2.6 and Pymol software were applied for molecular docking. Levels of the proinflammatory cytokines IL-6, TNFα and IL-1ß were measured by ELISA, while mRNA expression levels of intercellular adhesion molecule 1 (ICAM-1), vascular endothelial growth factor A (VEGFA) and IFN gamma (IFNG) were detected by real-time quantitative reverse transcription PCR. The protein levels of the molecules involved in the NF-κB signalling pathway were validated by western blot analysis.Results. A total of 65 co-targets of SOP and COVID-19 were determined. GO and KEGG enrichment analyses suggested that SOP affected COVID-19 by regulating the IL-17 signalling pathway, TNF signalling pathway and other signalling pathways. The PPI network and molecular docking showed that p65, ICAM-1 and VEGFA were key targets of SOP against COVID-19 and the underlying mechanism was validated in A549 cells in vitro. SOP attenuated the LPS-induced production of TNF-α and IL-6 and downregulated the LPS-induced mRNA expression of ICAM-1, VEGFA and IFNG. Mechanistically, SOP pretreatment inhibited the phosphorylation of p65 and facilitated the activation of Nrf2.Conclusions. SOP has a potential therapeutic effect on COVID-19 through multiple pathways and targets, and inhibits the production of pro-inflammatory cytokines and molecules involved in the NF-κB signalling pathway.


Subject(s)
COVID-19 , Intercellular Adhesion Molecule-1 , Alkaloids , COVID-19/drug therapy , Cytokines/metabolism , Humans , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interleukin-6 , Lipopolysaccharides , Molecular Docking Simulation , NF-kappa B/metabolism , RNA, Messenger , Tumor Necrosis Factor-alpha , Vascular Endothelial Growth Factor A
8.
Arch Soc Esp Oftalmol (Engl Ed) ; 97(4): 184-190, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1851896

ABSTRACT

BACKGROUND AND OBJECTIVE: The SARS-CoV-2 pandemic has caused chaos in all health systems on the planet. It has been difficult to cope with COVID 19, but also to maintain the activity in other specialties. In ophthalmology, the scientific societies recommended providing urgent care, including the intravitreal treatment of patients with active neovascular age-related macular degeneration (AMD), since a delay in treatment implies a potential loss of visual acuity (VA). The main objective of this study was to measure the impact of the coronavirus lockdown on the activity and visual results in patients with neovascular AMD in Area 3 of Madrid. MATERIAL AND METHOD: A retrospective observational study was conducted of all patients with neovascular AMD who attended a consultation and/or received intravitreal treatment in the 3 months before the lockdown. RESULTS: In the 3 months before the lockdown, 144 patients with neovascular AMD were treated, of whom only 51 attended a consultation during the lockdown and, at 6 months after it, only 117 patients had resumed their follow-up. Mean VA before the lockdown was 58.0 ±â€¯23.7 letters and was statistically significantly reduced to 53.0 ±â€¯27.1 letters at 6 months after the lockdown. We also observed a significant decrease in the number of visits during the lockdown, despite the security measures implemented. CONCLUSIONS: Our study shows that patients with neovascular AMD have had a statistically significant decrease in VA due to the lockdown. A VA of almost 58 letters was reduced to 53 at 6 months after the lockdown. The percentage of patients who lost 15 or more letters doubled. We observed a 63.3% loss of temporary follow-up during the lockdown and a 14.58% loss of permanent follow-up at 6 months after the lockdown.


Subject(s)
COVID-19 , Wet Macular Degeneration , Angiogenesis Inhibitors/therapeutic use , Communicable Disease Control , Humans , Intravitreal Injections , Pandemics , SARS-CoV-2 , Vascular Endothelial Growth Factor A , Visual Acuity , Wet Macular Degeneration/drug therapy
9.
Retina ; 42(8): 1529-1535, 2022 08 01.
Article in English | MEDLINE | ID: covidwho-1831443

ABSTRACT

PURPOSE: Evaluating the impact of delayed care, secondary to coronavirus disease 2019 (COVID-19) pandemic lockdowns, on visual acuity in previously treated neovascular age-related macular degeneration (nAMD) patients. METHODS: This was a multicenter, retrospective, study of patients with nAMD previously treated with anti-VEGF injections who were followed up during 2019 (pre-COVID-19) and compared with patients with nAMD during 2020 (COVID-19). RESULTS: A total of 1,192 patients with nAMD with a mean age of 81.5 years met the inclusion criteria. Of these, 850 patients were assessed in 2019 (pre-COVID-19) and 630 patients were assessed in 2020 (COVID-19). Three hundred eight patients were assessed through both 2019 and 2020 and thus were included in both cohorts. There was no significant difference between 2020 and 2019 in baseline and change in best-corrected visual acuity (BCVA; P = 0.342 and P = 0.911, respectively). The mean number of anti-VEGF injections was significantly lower (5.55 vs. 6.13, P < 0.01), with constant lower ratio of injections per patient in the COVID-19 period. Baseline BCVA (0.859, P < 0.01), number of injections (-0.006, P = 0.01), and age (0.003, P < 0.01) were predictors of final BCVA. CONCLUSION: In patients with nAMD, delayed care secondary to COVID-19 pandemic lockdowns has no statistically significant impact on BCVA. Best-corrected visual acuity, older age, and lower number of yearly anti-VEGF injections are predictors for decrease BCVA.


Subject(s)
COVID-19 , Wet Macular Degeneration , Aged, 80 and over , Angiogenesis Inhibitors/therapeutic use , COVID-19/epidemiology , Communicable Disease Control , Humans , Intravitreal Injections , Pandemics , Ranibizumab/therapeutic use , Retrospective Studies , Treatment Outcome , Vascular Endothelial Growth Factor A , Visual Acuity , Wet Macular Degeneration/drug therapy
11.
Front Endocrinol (Lausanne) ; 13: 845404, 2022.
Article in English | MEDLINE | ID: covidwho-1809370

ABSTRACT

The borderless transmission of coronavirus remains uncontrolled globally. The uncharted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant reduces the therapeutic efficacy of vaccines against coronavirus disease 2019 (COVID-19). Clinical observations suggest that tumour cases are highly infected with coronavirus, possibly due to immunologic injury, causing a higher COVID-19-related death toll. Presently, screening of candidate medication against coronavirus is in progress. Mogroside V, a bioactive ingredient of Siraitia grosvenorii, has been reported in China to have lung-protective and anticancer effects. The current study used network pharmacology and molecular docking to unlock the potential drug targets and remedial mechanisms of mogroside V against patients with ovarian cancer with COVID-19. We identified 24 related targets of mogroside V in patients with ovarian cancer and COVID-19 and characterised another 10 core targets of mogroside V against COVID-19 ovarian cancer, including Jun, IL2, HSP90AA1, AR, PRKCB, VEGFA, TLR9, TLR7, STAT3, and PRKCA. The core targets' biological processes and signalling pathways were revealed by enrichment analysis. Molecular docking suggested favourable docking between core target protein and mogroside V, including vascular endothelial growth factor A (VEGFA). These findings indicated that mogroside V might be a potential therapeutic agent in the mitigation of COVID-19 ovarian cancer.


Subject(s)
COVID-19 , Ovarian Neoplasms , COVID-19/drug therapy , Female , Humans , Molecular Docking Simulation , Ovarian Neoplasms/drug therapy , SARS-CoV-2 , Triterpenes , Vascular Endothelial Growth Factor A
12.
Methods Mol Biol ; 2475: 339-350, 2022.
Article in English | MEDLINE | ID: covidwho-1802606

ABSTRACT

Vascular endothelial growth factor (VEGF) stimulates vascular permeability in a variety of human pathologies, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema, sepsis, acute lung injury, and acute respiratory distress syndrome. Comprehensive investigation of the molecular mechanisms of VEGF-induced vascular permeability has been hindered by the lack of in vivo models that easily facilitate genetic manipulation studies in real time. To address this need, we generated a heat-inducible VEGF transgenic zebrafish model of vascular permeability. Here, we describe how this zebrafish model can be used to monitor VEGF-induced vascular permeability through live in vivo imaging to identify genetic regulators that play key roles in vascular barrier integrity in physiological conditions and human disease processes.


Subject(s)
COVID-19 , Capillary Permeability , Animals , Capillary Permeability/physiology , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factors/metabolism , Zebrafish/genetics , Zebrafish/metabolism
13.
EMBO Mol Med ; 14(5): e14844, 2022 05 09.
Article in English | MEDLINE | ID: covidwho-1776709

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can cause gastrointestinal (GI) symptoms that often correlate with the severity of COVID-19. Here, we explored the pathogenesis underlying the intestinal inflammation in COVID-19. Plasma VEGF level was particularly elevated in patients with GI symptoms and significantly correlated with intestinal edema and disease progression. Through an animal model mimicking intestinal inflammation upon stimulation with SARS-CoV-2 spike protein, we further revealed that VEGF was over-produced in the duodenum prior to its ascent in the circulation. Mechanistically, SARS-CoV-2 spike promoted VEGF production through activating the Ras-Raf-MEK-ERK signaling in enterocytes, but not in endothelium, and inducing permeability and inflammation. Blockage of the ERK/VEGF axis was able to rescue vascular permeability and alleviate intestinal inflammation in vivo. These findings provide a mechanistic explanation and therapeutic targets for the GI symptoms of COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Enterocytes/metabolism , Humans , Inflammation/metabolism , Spike Glycoprotein, Coronavirus , Vascular Endothelial Growth Factor A
14.
Biomolecules ; 12(3)2022 02 26.
Article in English | MEDLINE | ID: covidwho-1760347

ABSTRACT

Vascular endothelial growth factors (VEGFs) are the key regulators of blood and lymphatic vessels' formation and function. Each of the proteins from the homologous family VEGFA, VEGFB, VEGFC and VEGFD employs a core cysteine-knot structural domain for the specific interaction with one or more of the cognate tyrosine kinase receptors. Additional diversity is exhibited by the involvement of neuropilins-transmembrane co-receptors, whose b1 domain contains the binding site for the C-terminal sequence of VEGFs. Although all relevant isoforms of VEGFs that interact with neuropilins contain the required C-terminal Arg residue, there is selectivity of neuropilins and VEGF receptors for the VEGF proteins, which is reflected in the physiological roles that they mediate. To decipher the contribution made by the C-terminal sequences of the individual VEGF proteins to that functional differentiation, we determined structures of molecular complexes of neuropilins and VEGF-derived peptides and examined binding interactions for all neuropilin-VEGF pairs experimentally and computationally. While X-ray crystal structures and ligand-binding experiments highlighted similarities between the ligands, the molecular dynamics simulations uncovered conformational preferences of VEGF-derived peptides beyond the C-terminal arginine that contribute to the ligand selectivity of neuropilins. The implications for the design of the selective antagonists of neuropilins' functions are discussed.


Subject(s)
Neuropilins , Vascular Endothelial Growth Factor A , Ligands , Neuropilins/chemistry , Neuropilins/genetics , Neuropilins/metabolism , Peptides , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factors
15.
J Allergy Clin Immunol ; 149(5): 1592-1606.e16, 2022 05.
Article in English | MEDLINE | ID: covidwho-1739828

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening sequela of severe acute respiratory syndrome coronavirus 2 infection characterized by hyperinflammation and multiorgan dysfunction. Although hyperinflammation is a prominent manifestation of MIS-C, there is limited understanding of how the inflammatory state of MIS-C differs from that of well-characterized hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH). OBJECTIVES: We sought to compare the qualitative and quantitative inflammatory profile differences between patients with MIS-C, coronavirus disease 2019, and HLH. METHODS: Clinical data abstraction from patient charts, T-cell immunophenotyping, and multiplex cytokine and chemokine profiling were performed for patients with MIS-C, patients with coronavirus disease 2019, and patients with HLH. RESULTS: We found that both patients with MIS-C and patients with HLH showed robust T-cell activation, markers of senescence, and exhaustion along with elevated TH1 and proinflammatory cytokines such as IFN-γ, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10. In comparison, the amplitude of T-cell activation and the levels of cytokines/chemokines were higher in patients with HLH when compared with patients with MIS-C. Distinguishing inflammatory features of MIS-C included elevation in TH2 inflammatory cytokines such as IL-4 and IL-13 and cytokine mediators of angiogenesis, vascular injury, and tissue repair such as vascular endothelial growth factor A and platelet-derived growth factor. Immune activation and hypercytokinemia in MIS-C resolved at follow-up. In addition, when these immune parameters were correlated with clinical parameters, CD8+ T-cell activation correlated with cardiac dysfunction parameters such as B-type natriuretic peptide and troponin and inversely correlated with platelet count. CONCLUSIONS: Overall, this study characterizes unique and overlapping immunologic features that help to define the hyperinflammation associated with MIS-C versus HLH.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , COVID-19/complications , Child , Cytokines/metabolism , Humans , Ligands , Lymphohistiocytosis, Hemophagocytic/diagnosis , Systemic Inflammatory Response Syndrome , Vascular Endothelial Growth Factor A
16.
Front Immunol ; 13: 821681, 2022.
Article in English | MEDLINE | ID: covidwho-1708117

ABSTRACT

Peritoneal dialysis (PD) is a valuable 'home treatment' option, even more so during the ongoing Coronavirus pandemic. However, the long-term use of PD is limited by unfavourable tissue remodelling in the peritoneal membrane, which is associated with inflammation-induced angiogenesis. This appears to be driven primarily through vascular endothelial growth factor (VEGF), while the involvement of other angiogenic signaling pathways is still poorly understood. Here, we have identified the crucial contribution of mesothelial cell-derived angiogenic CXC chemokine ligand 1 (CXCL1) to peritoneal angiogenesis in PD. CXCL1 expression and peritoneal microvessel density were analysed in biopsies obtained by the International Peritoneal Biobank (NCT01893710 at www.clinicaltrials.gov), comparing 13 children with end-stage kidney disease before initiating PD to 43 children on chronic PD. The angiogenic potential of mesothelial cell-derived CXCL1 was assessed in vitro by measuring endothelial tube formation of human microvascular endothelial cells (HMECs) treated with conditioned medium from human peritoneal mesothelial cells (HPMCs) stimulated to release CXCL1 by treatment with either recombinant IL-17 or PD effluent. We found that the capillary density in the human peritoneum correlated with local CXCL1 expression. Both CXCL1 expression and microvessel density were higher in PD patients than in the age-matched patients prior to initiation of PD. Exposure of HMECs to recombinant CXCL1 or conditioned medium from IL-17-stimulated HPMCs resulted in increased endothelial tube formation, while selective inhibition of mesothelial CXCL1 production by specific antibodies or through silencing of relevant transcription factors abolished the proangiogenic effect of HPMC-conditioned medium. In conclusion, peritoneal mesothelium-derived CXCL1 promotes endothelial tube formation in vitro and associates with peritoneal microvessel density in uremic patients undergoing PD, thus providing novel targets for therapeutic intervention to prolong PD therapy.


Subject(s)
Chemokine CXCL1/metabolism , Neovascularization, Pathologic/pathology , Peritoneal Dialysis/methods , Peritoneum/blood supply , Renal Replacement Therapy/methods , COVID-19/pathology , Cells, Cultured , Child , Child, Preschool , Epithelium/metabolism , Humans , Infant , Interleukin-17/metabolism , Kidney Failure, Chronic/therapy , Peritoneum/pathology , Vascular Endothelial Growth Factor A/metabolism , Vascular Remodeling/physiology
17.
Retina ; 42(3): 465-475, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1706662

ABSTRACT

PURPOSE: To describe clinical and ophthalmologic features and outcomes of patients with coronavirus disease-19 with retinal vascular occlusions. METHODS: Retrospective multicenter case series and PubMed review of cases reported from March 2020 to September 2021. Outcome measures are as follows: type of occlusion, treatments, best-corrected visual acuity, and central macular thickness on optical coherence tomography. RESULTS: Thirty-nine patients were identified. Fifteen patients with a median age of 39 (30-67) years were included in the multicenter study. Vascular occlusions included central retinal vein occlusion (12 eyes), branch retinal vein occlusion (4 eyes), and central retinal artery occlusion (2 eyes). Three cases were bilateral. Baseline best-corrected visual acuity was 20/45 (no light perception-20/20). Baseline central macular thickness was 348.64 (±83) µm. Nine eyes received anti-vascular endothelial growth factor agents, dexamethasone intravitreal implant, or both. Final best-corrected visual acuity was 20/25 (no light perception-20/20), and central macular thickness was 273.7 ± 68 µm (follow-up of 19.6 ± 6 weeks). Among the 24 cases from the literature review, retinal vein occlusion was the predominant lesion. Clinical characteristics and outcomes were similar to those found in our series. CONCLUSION: Coronavirus disease-19-associated retinal vascular occlusions tend to occur in individuals younger than 60 years. Retinal vein occlusion is the most frequent occlusive event, and outcomes are favorable in most cases.


Subject(s)
COVID-19/diagnosis , Eye Infections, Viral/diagnosis , Retinal Vein Occlusion/diagnosis , SARS-CoV-2/isolation & purification , Adult , Aged , Angiogenesis Inhibitors/therapeutic use , COVID-19/drug therapy , COVID-19/virology , COVID-19 Nucleic Acid Testing , Dexamethasone/therapeutic use , Drug Implants , Eye Infections, Viral/drug therapy , Eye Infections, Viral/virology , Female , Fluorescein Angiography , Glucocorticoids/therapeutic use , Humans , Intravitreal Injections , Male , Middle Aged , Retinal Vein Occlusion/drug therapy , Retinal Vein Occlusion/virology , Retrospective Studies , SARS-CoV-2/genetics , Tomography, Optical Coherence , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Visual Acuity/physiology
18.
J Infect Dev Ctries ; 16(1): 101-111, 2022 Jan 31.
Article in English | MEDLINE | ID: covidwho-1704553

ABSTRACT

INTRODUCTION: During the evolution of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, several drug candidates have been proposed for repositioning towards a quest for more effective treatments. METHODOLOGY: We reviewed recent literature (Pubmed, Google, Clinicaltrials.gov), as of the middle of May 2021, for evidence regarding the potential benefit from poly(ADP-ribose)-polymerase inhibitors and vascular endothelial growth factor blockade in severe SARS-CoV-2 infection. RESULTS: poly(ADP-ribose)-polymerase inhibitors have been suggested as potential agents against coronavirus disease 2019 (COVID-19) by a variety of mechanisms. vascular endothelial growth factor-associated vascular permeability is implicated with increased vascular leakage and pulmonary oedema. Thus, anti-angiogenesis factors, such as bevacizumab are being investigated in critically ill COVID-19 patients. CONCLUSIONS: The synergistic potential of these two classes of inhibitors in severe COVID-19 management could be beneficial. Further research should be carried out in order to support this hypothesis.


Subject(s)
COVID-19 , Poly(ADP-ribose) Polymerase Inhibitors , Vascular Endothelial Growth Factor A , COVID-19/drug therapy , COVID-19/epidemiology , Humans , Pandemics , Patient Acuity , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , SARS-CoV-2 , Vascular Endothelial Growth Factor A/pharmacology
19.
Microbiol Spectr ; 10(1): e0167121, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1691404

ABSTRACT

The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARS-CoV-2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-α), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-to-patient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients. IMPORTANCE Lung vascular endothelial injury in SARS-CoV-2 patients is one of the most important causes of morbidity and mortality and has been linked to more severe complications including acute respiratory distress syndrome (ARDS) and subsequent death due to multiorgan failure. We have demonstrated that in eight consecutive patients with SARS-CoV-2, who were not selected for evidence of endothelial injury, the diluted plasma-induced intense lung microvascular damage, in vitro. Known endothelial barrier-disruptive agents and proposed mediators of increased endothelial permeability in SARS-CoV-2, induced changes in permeability that were smaller in magnitude and shorter in duration than plasma from patients with SARS-CoV-2. The effect on endothelial cell permeability of plasma from patients with SARS-CoV-2 was heat-labile. The main plasma factor that causes the increased endothelial permeability remains to be identified. Our study provides a possible approach for future studies to understand the underlying mechanisms leading to vascular injury in SARS-CoV-2 infections.


Subject(s)
COVID-19/blood , Capillary Permeability , Cytokines/blood , Lung/blood supply , SARS-CoV-2/physiology , Adult , Aged , COVID-19/physiopathology , COVID-19/virology , Endothelial Cells/virology , Female , Humans , Lung/virology , Male , Middle Aged , SARS-CoV-2/genetics , Tumor Necrosis Factor-alpha/blood , Vascular Endothelial Growth Factor A , Young Adult
20.
Int Ophthalmol ; 42(6): 1749-1762, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1653602

ABSTRACT

BACKGROUND AND OBJECTIVE: Age-related macular degeneration (AMD) is one of the most common reasons for blindness in the world today. The most common treatment for wet AMD is the intravitreal injections for inhibiting vascular-endothelial-derived growth factor (VEGF). This treatment usually involves multiple injections and thus multiple clinic visits, which not only causes increased cost on national health services but also causes exposure to the hospital environment, which is sometimes high risk considering current COVID crisis. The treatment, in spite of the above concerns, is usually effective. However, in some cases, either the medicine fails to produce the anticipated favourable outcome, resulting in waste of time, medication, efforts, and above all, psychological distress to the patients. Hence, early predictability of anatomical as well as functional effectiveness of the treatment appears to be a very desirable capability to have. METHOD: A machine learning approach using adaptive neuro-fuzzy inference system (ANFIS) of two-sample prediction model has been presented that requires only the baseline measurements and changes in visual acuity (VA) as well as macular thickness (MAC) after four months of treatment to estimate the values of VA and MAC at 8 and 12 months. In contrast to most of the AI techniques, ANFIS approach has shown the capability of the algorithm to work with very small dataset as well, which makes it a perfect candidate for the presented solution. RESULTS: The presented model has shown to have a very high accuracy (> 92%) and works in near-real-time scenarios. It has been converted into a smart phone App, OphnosisAMD, for convenient usage. With this App, the clinician can visualize the progression of the patient for a specific treatment and can decide on continuing or changing the treatment accordingly. The complete AI engine developed with the ANFIS algorithm is localized to the phone through the App, implying that there is no need for internet or cloud connectivity for this App to function. This makes it ideal for remote usage, especially under the current COVID scenarios. CONCLUSIONS: With a smart AI-based App on their fingertips, the presented system provides ample opportunity to the doctors to make a better decision based on the estimated progression, if the same drug is continued with (good/fair prognosis) or alternate treatment should be sought (bad prognosis). From a functional point of view, a prediction algorithm is triggered through simple entry of the relevant parameters (baseline and 4 months only). No internet/cloud connectivity is needed since the algorithm and the trained network are fully embedded in the App locally. Hence, using the App in remote and/or non-connected isolated areas is possible, especially in the secluded patients during the COVID scenarios.


Subject(s)
COVID-19 , Cell Phone , Wet Macular Degeneration , Aged, 80 and over , Angiogenesis Inhibitors/therapeutic use , Artificial Intelligence , Humans , Intravitreal Injections , Prognosis , Ranibizumab , Treatment Outcome , Vascular Endothelial Growth Factor A , Wet Macular Degeneration/diagnosis , Wet Macular Degeneration/drug therapy
SELECTION OF CITATIONS
SEARCH DETAIL