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1. Microvascular dysfunction in COVID-19: the MYSTIC study

Author

Philipp Kümpers, Jan Sackarnd, Gerold Thölking, Hans Vink, Phil-Robin Tepasse, Andreas Gröschel, Joachim Kuhn, Irina Osiaevi, Konrad Buscher, Hermann Pavenstädt, Alexandros Rovas, Manfred Fobker, Ulrich Göbel, Stephan Braune, Fysiologie, and RS: Carim - B05 Cerebral small vessel disease

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, ARDS, Cancer Research, vasculature, Intravital Microscopy, Angiogenesis, Physiology, GLYCOCALYX, Clinical Biochemistry, endothelial glycocalyx, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Microcirculation, Glycocalyx, PROTECTS, 03 medical and health sciences, 0302 clinical medicine, Sublingual microscopy, medicine, Humans, Prospective Studies, Endothelial dysfunction, Aged, Inflammation, Original Paper, business.industry, COVID-19, Middle Aged, medicine.disease, Endotheliopathy, ADAMTS13, Healthy Volunteers, Perfusion, Vascular endothelial growth factor A, ANGIOPOIETIN-1, 030104 developmental biology, Cross-Sectional Studies, Treatment Outcome, Area Under Curve, Female, Endothelium, Vascular, business, Intravital microscopy, Follow-Up Studies
Abstract

Rationale Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. Objectives To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. Methods Hospitalized adult patients with moderate-to-severe or critical COVID-19 (n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity (VRBC), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. Measurements and main results COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4–6 µm), and also significant reductions of VRBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. Conclusions Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.

Published
2021

2. COVID-19 and Cancer Diseases—The Potential of Coriolus versicolor Mushroom to Combat Global Health Challenges.

Author

Jędrzejewski, Tomasz, Pawlikowska, Małgorzata, Sobocińska, Justyna, and Wrotek, Sylwia

Subjects
TRAMETES versicolor, COVID-19, WORLD health, MEDICAL research, CHINESE medicine, MUSHROOMS, PAPILLOMAVIRUSES
Abstract

Coriolus versicolor (CV) is a common species from the Polyporaceae family that has been used in traditional Chinese herbal medicine for over 2000 years. Among well-described and most active compounds identified in CV are polysaccharopeptides, such as polysaccharide peptide (PSP) and Polysaccharide-K (PSK, krestin), which, in some countries, are already used as an adjuvant agent in cancer therapy. In this paper, research advances in the field of anti-cancer and anti-viral action of CV are analyzed. The results of data obtained in in vitro and in vivo studies using animal models as well as in clinical research trials have been discussed. The present update provides a brief overview regarding the immunomodulatory effects of CV. A particular focus has been given to the mechanisms of direct effects of CV on cancer cells and angiogenesis. A potential use of CV compounds in anti-viral treatment, including therapy against COVID-19 disease, has also been analyzed based on the most recent literature. Additionally, the significance of fever in viral infection and cancer has been debated, providing evidence that CV affects this phenomenon. [ABSTRACT FROM AUTHOR]

Published
2023
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3. COVID-19 and Pulmonary Angiogenesis: The Possible Role of Hypoxia and Hyperinflammation in the Overexpression of Proteins Involved in Alveolar Vascular Dysfunction.

Author

Miggiolaro, Anna Flavia Ribeiro Santos, da Silva, Felipe Paes Gomes, Wiedmer, David Batista, Godoy, Thiago Mateus, Borges, Nicolas Henrique, Piper, Giulia Werner, Oricil, Alessandro G. G., Klein, Carolline Konzen, Hlatchuk, Elisa Carolina, Dagostini, Júlio César H., Collete, Mariana, Arantes, Mayara Pezzini, D'Amico, Raissa C., Dutra, Anderson A., de Azevedo, Marina Luise Viola, and de Noronha, Lucia

Subjects
IMMUNOHISTOCHEMISTRY techniques, NEOVASCULARIZATION, INFLAMMATION, COVID-19, ENDOTHELIUM diseases
Abstract

COVID-19 has been considered a vascular disease, and inflammation, intravascular coagulation, and consequent thrombosis may be associated with endothelial dysfunction. These changes, in addition to hypoxia, may be responsible for pathological angiogenesis. This research investigated the impact of COVID-19 on vascular function by analyzing post-mortem lung samples from 24 COVID-19 patients, 10 H1N1pdm09 patients, and 11 controls. We evaluated, through the immunohistochemistry technique, the tissue immunoexpressions of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis (ICAM-1, ANGPT-2, and IL-6, IL-1β, vWF, PAI-1, CTNNB-1, GJA-1, VEGF, VEGFR-1, NF-kB, TNF-α and HIF-1α), along with the histopathological presence of microthrombosis, endothelial activation, and vascular layer hypertrophy. Clinical data from patients were also observed. The results showed that COVID-19 was associated with increased immunoexpression of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis compared to the H1N1 and CONTROL groups. Microthrombosis and vascular layer hypertrophy were found to be more prevalent in COVID-19 patients. This study concluded that immunothrombosis and angiogenesis might play a key role in COVID-19 progression and outcome, particularly in patients who die from the disease. [ABSTRACT FROM AUTHOR]

Published
2023
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4. COVID-19 and Cancer Diseases—The Potential of Coriolus versicolor Mushroom to Combat Global Health Challenges

Author

Tomasz Jędrzejewski, Małgorzata Pawlikowska, Justyna Sobocińska, and Sylwia Wrotek

Subjects
Coriolus versicolor, cancer, COVID-19, immunomodulation, angiogenesis, inflammation, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Coriolus versicolor (CV) is a common species from the Polyporaceae family that has been used in traditional Chinese herbal medicine for over 2000 years. Among well-described and most active compounds identified in CV are polysaccharopeptides, such as polysaccharide peptide (PSP) and Polysaccharide-K (PSK, krestin), which, in some countries, are already used as an adjuvant agent in cancer therapy. In this paper, research advances in the field of anti-cancer and anti-viral action of CV are analyzed. The results of data obtained in in vitro and in vivo studies using animal models as well as in clinical research trials have been discussed. The present update provides a brief overview regarding the immunomodulatory effects of CV. A particular focus has been given to the mechanisms of direct effects of CV on cancer cells and angiogenesis. A potential use of CV compounds in anti-viral treatment, including therapy against COVID-19 disease, has also been analyzed based on the most recent literature. Additionally, the significance of fever in viral infection and cancer has been debated, providing evidence that CV affects this phenomenon.

Published
2023
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5. Adhatoda Vasica attenuates inflammatory and hypoxic responses in preclinical mouse models: potential for repurposing in COVID-19-like conditions.

Author

Gheware, Atish, Dholakia, Dhwani, Kannan, Sadasivam, Panda, Lipsa, Rani, Ritu, Pattnaik, Bijay Ranjan, Jain, Vaibhav, Parekh, Yash, Enayathullah, M. Ghalib, Bokara, Kiran Kumar, Subramanian, Venkatesan, Mukerji, Mitali, Agrawal, Anurag, and Prasher, Bhavana

Subjects
PULMONARY fibrosis, LABORATORY mice, ANIMAL models in research, INFLAMMATION, OVERALL survival, SURVIVAL rate
Abstract

Background: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models.Methods: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication.Results: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-β1 (TGF-β1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-β1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2.Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions. [ABSTRACT FROM AUTHOR]

Published
2021
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7. Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

Author

Shawn M. Burgess, Luke H. Hoeppner, Matteo Astone, Wuhong Pei, Zhu Zhu, David A. Frank, Sk Kayum Alam, and Li Wang

Subjects
STAT3 Transcription Factor, Vascular Endothelial Growth Factor A, Endothelium, Angiogenesis, Neuroscience (miscellaneous), Medicine (miscellaneous), Inflammation, Vascular permeability, Lung injury, Article, stat3, General Biochemistry, Genetics and Molecular Biology, Capillary Permeability, Mice, chemistry.chemical_compound, Immunology and Microbiology (miscellaneous), Pathology, medicine, Animals, Humans, RB1-214, Phosphorylation, STAT3, vascular permeability, vegf, Barrier function, Mice, Knockout, biology, Janus Kinase 2, Intercellular Adhesion Molecule-1, zebrafish, Cell biology, Mice, Inbred C57BL, Vascular endothelial growth factor, pyrimethamine, medicine.anatomical_structure, covid-19, chemistry, biology.protein, Medicine, Endothelium, Vascular, CRISPR-Cas Systems, medicine.symptom, Research Article, Signal Transduction
Abstract

Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, including cancer, stroke, cardiovascular disease, retinal conditions and COVID-19-associated pulmonary edema, sepsis and acute lung injury. Understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics to inhibit vascular permeability, while preserving tissue-restorative angiogenesis. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. We show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9-generated Stat3 knockout zebrafish. Intercellular adhesion molecule 1 (ICAM-1) expression is transcriptionally regulated by STAT3, and VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved antimicrobial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse and human endothelium. Collectively, our findings suggest that VEGF/VEGFR-2/JAK2/STAT3 signaling regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability. This article has an associated First Person interview with the first author of the paper., Summary: Genetic STAT3 ablation in mice and VEGF-inducible zebrafish reveals that VEGF signals through STAT3 to promote vascular permeability. Pyrimethamine reduces VEGF-induced permeability in animal models.

Published
2021