scholarly journals Targeting the Complement Cascade in the Pathophysiology of COVID-19 Disease

2021 ◽  
Vol 10 (10) ◽  
pp. 2188
Author(s):  
Nicole Ng ◽  
Charles A. Powell
Keyword(s):  
Clinical Trials ◽  
Endothelial Dysfunction ◽  
Severe Acute Respiratory Syndrome ◽  
Disease Progression ◽  
Organ Dysfunction ◽  
Innate Immune ◽  
Complement Cascade ◽  
Significant Morbidity ◽  
Immune Pathways ◽  
Complement Pathways

Severe coronavirus disease 2019 causes multi-organ dysfunction with significant morbidity and mortality. Mounting evidence implicates maladaptive over-activation of innate immune pathways such as the complement cascade as well as endothelial dysfunction as significant contributors to disease progression. We review the complement pathways, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on these pathways, and promising therapeutic targets in clinical trials.

Primary Prophylaxis in Sickle Cell Disease: Is It Feasible? Is It Effective?

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 434-439 ◽  
Author(s):  
Alexis A. Thompson
Keyword(s):  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Disease Progression ◽  
Organ Dysfunction ◽  
Sickle Cell ◽  
Primary Prophylaxis ◽  
Organ Injury ◽  
Clear Understanding ◽  
Cell Disease ◽  
Laboratory Tool

Abstract Consideration of primary prophylaxis to prevent complications of sickle cell disease (SCD) requires a clear understanding of the earliest manifestations of SCD-related organ injury, a reliable clinical or laboratory tool to detect organ dysfunction, and evidence that an intervention instituted in the presymptomatic state can mitigate disease progression. This review examines the pathophysiology of SCD in organs that may be potential targets for intervention, our current capacity to evaluate early SCD manifestations, results of clinical trials, and opportunities for future interventions.

P717Glucagon-like peptide 1 (GLP-1) improves endothelial dysfunction and vascular inflammation in polymicrobial sepsis induced by cecal ligation and puncture (CLP)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Steven ◽  
J Helmstaedter ◽  
F Pawelke ◽  
K Filippou ◽  
K Frenies ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Endothelial Dysfunction ◽  
Knockout Mice ◽  
Vascular Inflammation ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Glucose Levels ◽  
Dpp4 Inhibitor ◽  
Cardioprotective Effects

Abstract Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.

scholarly journals Prolonged activation of innate immune pathways by a polyvalent STING agonist

2021 ◽  
Author(s):  
Suxin Li ◽  
Min Luo ◽  
Zhaohui Wang ◽  
Qiang Feng ◽  
Jonathan Wilhelm ◽  
...  
Keyword(s):  
Innate Immune ◽  
Immune Pathways

scholarly journals Anti-phospholipid syndrome and COVID-19 thrombosis: connecting the dots

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Moon Ley Tung ◽  
Bryce Tan ◽  
Robin Cherian ◽  
Bharatendu Chandra
Keyword(s):  
Endothelial Dysfunction ◽  
Severe Acute Respiratory Syndrome ◽  
Potential Role ◽  
Molecular Mimicry ◽  
Thromboembolic Events ◽  
The Past ◽  
High Prevalence ◽  
Connecting The Dots ◽  
Anti Phospholipid Syndrome

Abstract As the coronavirus disease 2019 (COVID-19) pandemic, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide, it has emerged as a leading cause of mortality, resulting in >1 million deaths over the past 10 months. The pathophysiology of COVID-19 remains unclear, posing a great challenge to the medical management of patients. Recent studies have reported an unusually high prevalence of thromboembolic events in COVID-19 patients, although the mechanism remains elusive. Several studies have reported the presence of aPLs in COVID-19 patients. We have noticed similarities between COVID-19 and APS, which is an autoimmune prothrombotic disease that is often associated with an infective aetiology. Molecular mimicry and endothelial dysfunction could plausibly explain the mechanism of thrombogenesis in acquired APS. In this review, we discuss the clinicopathological similarities between COVID-19 and APS, and the potential role of therapeutic targets based on the anti-phospholipid model for COVID-19 disease.

scholarly journals Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Basma Basha ◽  
Samson Mathews Samuel ◽  
Chris R. Triggle ◽  
Hong Ding
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Clinical Trials ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Therapeutic Agents ◽  
Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

Interaction Between Adaptive and Innate Immune Pathways in the Pathogenesis of Atopic Asthma

CHEST Journal ◽  
2011 ◽  
Vol 139 (5) ◽  
pp. 1165-1171 ◽  
Author(s):  
Patrick G. Holt ◽  
Peter D. Sly
Keyword(s):  
Innate Immune ◽  
Atopic Asthma ◽  
Immune Pathways

COVID-19: Are Experimental Drugs Cure or Ill?

2021 ◽  
Vol 16 ◽  
Author(s):  
Bensu Karahalil ◽  
Aylin Elkama
Keyword(s):  
Clinical Trials ◽  
Severe Acute Respiratory Syndrome ◽  
Adverse Effects ◽  
Antiviral Treatment ◽  
Herd Immunity ◽  
Mortality Rates ◽  
Death Rates ◽  
Experimental Drugs ◽  
Combined Use ◽  
The World

Background: Coronavirus disease 2019 (COVID-19) is a new strain of coronavirus. It is characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has quickly influenced all over the world since it spreads easily. Common symptoms are fever, cough, difficulty in breathing and muscle aches. Despite the urgent need to find an effective antiviral treatment, already available agents are being used alone or in combination all over the world. At the beginning of the pandemic, death rates of infection caused by COVID-19 are high but "is COVID-19 responsible for all deaths?", or “are there any contributions of the frequently used drugs in this period to these deaths?” Surely herd immunity plays a major role and has the contribution in the decline in mortality rates. Meanwhile, it is kept in mind that due to safety concerns, changes have also been made to the dosage and combined use of frequently used drugs. Objective: In this review, answers to two questions above and the safety of treatments, toxicities of agents involving chloroquine, hydroxychloroquine, remdesivir, favipiravir, lopiravir/ritonavir, sarilumab, tocilizumab, siltuximab, corticosteroids and bromhexine which are the most frequently used in both Turkey and all over the world will be summarized. Conclusion: Among these drugs favipiravir seems the most promising drug due to more tolerable adverse effects. More clinical trials with large sample sizes are needed to find the most effective and safe drug for COVID-19 treatment.

Using A 21-Year Real-World Database from a Private Cardiologist's Practice to Test the Hypothesis that Combining Pharmacological Therapies (Carvedilol, Spironolactone and Statins) with Weight Loss May Benefit Patients with HFpEF

2020 ◽  
pp. 1-9
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Weight Loss ◽  
Clinical Trials ◽  
Endothelial Dysfunction ◽  
Combination Therapy ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Left Ventricular ◽  
Lv Diastolic Dysfunction

Heart Failure with preserved Ejection Fraction (HFpEF) is a clinical syndrome in which patients have symptoms of Heart Failure (HF), such as dyspnea and fatigue, a Left Ventricular Ejection Fraction (LVEF) ≥ 50% and evidence of cardiac dysfunction as a cause of symptoms, such as abnormal Left Ventricular (LV) diastolic dysfunction with elevated filling pressures. Besides LV diastolic dysfunction, recent investigations suggest a more complex and heterogeneous pathophysiology, including systolic reserve abnormalities, chronotropic incompetence, stiffening of ventricular tissue, atrial dysfunction, secondary Pulmonary Arterial Hypertension (PAH), impaired vasodilatation and endothelial dysfunction. Unlike Heart Failure with Reduced Ejection Fraction (HFrEF), clinical trials over the years have not yet identified effective treatments that reduce mortality in patients with HFpEF. A database on use of carvedilol in a private cardiologist's practice was begun in 1997 and concluded at the end of 2018. We used this database to test the hypothesis that combining pharmacological interventions to address diastolic dysfunction (carvedilol), volume overload (spironolactone/eplerenone) and endothelial dysfunction (statins) with weight loss may benefit patients with HFpEF. We report analysis of 335 patients with HFpEF comprised of 61% female (mean age 74 ± 8) and 39% males (mean age 72 ± 7). Initial EF ranged between 50 and 77% with mean EF of 57 ± 6%. Only 15 patients were changed to metoprolol succinate, verapamil or diltiazem because of adverse side effects. Two hundred and twenty of the patients were in normal sinus rhythm when started on carvedilol, spironolactone/eplerenone and statin therapy with weight loss counseling. After 5 years, 191 patients were still on combination therapy, and only 31 (17%) had developed Atrial Fibrillation (AF). Compared to previous HFpEF trials reporting a 32% risk of developing atrial fibrillation after 4 years, our combination therapy significantly (p < 0.05) reduced the risk of developing AF over 5 years. Thus, irrespective of age and sex with comorbidities of type 2 Diabetes Mellitus (DM) and Chronic Kidney Disease (CKD), patients with HFpEF can be managed successfully with carvedilol, spironolactone/eplerenone and statins with a clinical benefit being a reduced risk of developing AF. We consider these data hypothesis-generating and hope these results will be tested further in database analyses and clinical trials.

scholarly journals Distinct Roles of Hemocytes at Different Stages of Infection by Dengue and Zika Viruses in Aedes aegypti Mosquitoes

2021 ◽  
Vol 12 ◽  
Author(s):  
Thiago H. J. F. Leite ◽  
Álvaro G. A. Ferreira ◽  
Jean-Luc Imler ◽  
João T. Marques
Keyword(s):  
Aedes Aegypti ◽  
Cellular Responses ◽  
Innate Immune ◽  
Mosquito Vector ◽  
Phagocytic Function ◽  
Systemic Dissemination ◽  
Latex Beads ◽  
Medical Importance ◽  
Immune Pathways

Aedes aegypti mosquitoes are vectors for arboviruses of medical importance such as dengue (DENV) and Zika (ZIKV) viruses. Different innate immune pathways contribute to the control of arboviruses in the mosquito vector including RNA interference, Toll and Jak-STAT pathways. However, the role of cellular responses mediated by circulating macrophage-like cells known as hemocytes remains unclear. Here we show that hemocytes are recruited to the midgut of Ae. aegypti mosquitoes in response to DENV or ZIKV. Blockade of the phagocytic function of hemocytes using latex beads induced increased accumulation of hemocytes in the midgut and a reduction in virus infection levels in this organ. In contrast, inhibition of phagocytosis by hemocytes led to increased systemic dissemination and replication of DENV and ZIKV. Hence, our work reveals a dual role for hemocytes in Ae. aegypti mosquitoes, whereby phagocytosis is not required to control viral infection in the midgut but is essential to restrict systemic dissemination. Further understanding of the mechanism behind this duality could help the design of vector-based strategies to prevent transmission of arboviruses.

Sign in / Sign up

Export Citation Format

Share Document