Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

Currently, the COVID-19 pandemic is an international challenge, largely due to lack of effective therapies. Pharmacotherapy has not yet been able to find a definitive treatment for COVID-19. Since SARS-CoV-2 affects several organs, treatment strategies that target the virus in a wider range are expected to be ultimately more successful. To this end, a two-step treatment strategy has been presented. In the first phase of the disease, when the patient is newly infected with the virus and the cytokine storm has not yet been developed, a chimeric peptide is used to inhibit virus entry into the host cell cytosol (by inhibiting endosomal pH acidification) and viral replication. After the virus entry and decrease of angiotensin converting enzyme 2 (ACE2) level, some people are unable to properly compensate for the ACE2 pathway and progress toward the cytokine storm. In the beginning of the cytokine storm, sACE2 protein is very effective in regulating the immune system toward the anti-inflammatory pathway, including M2 macrophages. Hence, the genes of 8P9R chimeric peptide and sACE2 would be inserted in an episomal vector with a separate promoter for each gene: the chimeric peptide gene promoter is a CMV promoter, while the sACE2 gene promoter is a NF-κB-sensitive promoter. The NF-κB-sensitive promoter induces the expression of sACE2 gene soon after elevation of NF-κB which is the main transcription factor of inflammatory genes. Thus, as the expression of inflammatory cytokines increases, the expression of sACE2 increases simultaneously. In this condition, sACE2 can prevent the cytokine storm by inhibiting the pro-inflammatory pathways. To deliver the designed vector to the target cells, mesenchymal stem cell-derived (MSC-derived) exosome-liposome hybrids are used. Herein, the strategy can be considered as a personalized clinical therapy for COVID-19, that can prevent morbidity and mortality in the future.

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Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

Cells ◽

10.3390/cells10071585 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1585

Author(s):

Annamaria Paolini ◽

Rebecca Borella ◽

Sara De Biasi ◽

Anita Neroni ◽

Marco Mattioli ◽

...

Keyword(s):

Cell Death ◽

Immune Cells ◽

Viral Infections ◽

Virus Entry ◽

Therapeutic Strategies ◽

The Other ◽

Cytokine Storm ◽

Cytokines And Chemokines ◽

Cell Death Mechanisms ◽

The One

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.

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Integrin Dependence of Brain Natriuretic Peptide Gene Promoter Activation by Mechanical Strain

Journal of Biological Chemistry ◽

10.1074/jbc.m001660200 ◽

2000 ◽

Vol 275 (27) ◽

pp. 20355-20360 ◽

Cited By ~ 32

Author(s):

Faquan Liang ◽

Amha Atakilit ◽

David G. Gardner

Keyword(s):

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Mechanical Strain ◽

Gene Promoter ◽

Promoter Activation ◽

Peptide Gene

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Molecular Signaling and Cellular Pathways for Virus Entry

ISRN Virology ◽

10.5402/2013/306595 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Pei-I Chi ◽

Hung-Jen Liu

Keyword(s):

Signaling Pathways ◽

Viral Entry ◽

Virus Entry ◽

Host Cells ◽

Target Cells ◽

Molecular Signaling ◽

Cellular Processes ◽

Cellular Pathways ◽

Host Life ◽

Endocytic Vesicles

The cell signaling plays a pivotal role in regulating cellular processes and is often manipulated by viruses as they rely on the functions offered by cells for their propagation. The first stage of their host life is to pass the genetic materials into the cell. Although some viruses can directly penetrate into cytosol, in fact, most virus entry into their host cells is through endocytosis. This machinery initiates with cell type specific cellular signaling pathways, and the signaling compounds can be proteins, lipids, and carbohydrates. The activation can be triggered in a very short time after virus binds on target cells, such as receptors. The signaling pathways involved in regulation of viral entry are wide diversity that often cross-talk between different endocytosis results. Furthermore, some viruses have the ability to use the multiple internalization pathways which leads to the regulation being even more complex. In this paper, we discuss some recent advances in our understanding of cellular pathways for virus entry, molecular signaling during virus entry, formation of endocytic vesicles, and the traffic.

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Exosomal MicroRNA: Diagnostic Marker and Therapeutic Tool for Lung Diseases

Current Pharmaceutical Design ◽

10.2174/1381612827666210608150640 ◽

2021 ◽

Vol 27 ◽

Author(s):

Yu Hua ◽

Yan Ding ◽

Yapeng Hou ◽

Yanhong Liu ◽

Kejun Mao ◽

...

Keyword(s):

Lung Diseases ◽

Diagnostic Marker ◽

Treatment Strategies ◽

Diagnostic Methods ◽

Chronic Obstructive ◽

Target Cells ◽

High Morbidity ◽

Therapeutic Tool ◽

Obstructive Pulmonary Disease ◽

Exosomal Microrna

: Lung diseases are common clinical illnesses with high morbidity and mortality, which seriously threaten human health. In recent years, increasing evidence suggests that exosomes play a pivotal role in intercellular communication by delivering their cargo to pulmonary target cells，such as microRNAs. Physiologically, exosomes have been shown to be a critical mediator in maintaining homeostasis function in the complex thin-walled lung tissue and airway structure. Apart from being a diagnostic and prognostic biomarker, exosomes also participate in the progression of some lung diseases, such as chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, acute lung injury, lung cancer, interstitial lung disease, and tuberculosis. Here, we summarize the recent findings on the involvement of exosomes and exosomal microRNAs in the pathogenesis, diagnosis, and therapy of lung diseases, aiming to provide more information to discover novel diagnostic methods and treatment strategies for these disorders.

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Emerging Prevention and Treatment Strategies to Control COVID-19

Pathogens ◽

10.3390/pathogens9060501 ◽

2020 ◽

Vol 9 (6) ◽

pp. 501 ◽

Cited By ~ 2

Author(s):

Vipul K. Singh ◽

Abhishek Mishra ◽

Shubhra Singh ◽

Premranjan Kumar ◽

Manisha Singh ◽

...

Keyword(s):

Early Stage ◽

Treatment Options ◽

Treatment Strategies ◽

Clinical Development ◽

Definitive Treatment ◽

Prevention Therapy ◽

Potential Alternative ◽

Novel Coronavirus ◽

Global Threat ◽

New Vaccines

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has now become a serious global threat after inflicting more than 8 million infections and 425,000 deaths in less than 6 months. Currently, no definitive treatment or prevention therapy exists for COVID-19. The unprecedented rise of this pandemic has rapidly fueled research efforts to discover and develop new vaccines and treatment strategies against this novel coronavirus. While hundreds of vaccines/therapeutics are still in the preclinical or early stage of clinical development, a few of them have shown promising results in controlling the infection. Here, in this review, we discuss the promising vaccines and treatment options for COVID-19, their challenges, and potential alternative strategies.

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Distinct signalling pathways mediate the cAMP response element (CRE)-dependent activation of the calcitonin gene-related peptide gene promoter by cAMP and nerve growth factor

Biochemical Journal ◽

10.1042/0264-6021:3450233 ◽

2000 ◽

Vol 345 (2) ◽

pp. 233 ◽

Cited By ~ 21

Author(s):

Karen FREELAND ◽

Yu-Zhen LIU ◽

David S. LATCHMAN

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Gene Promoter ◽

Signalling Pathways ◽

Camp Response Element ◽

Response Element ◽

Nerve Growth ◽

Related Peptide ◽

Calcitonin Gene ◽

Peptide Gene

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Current Strategies in the Treatment of Intracranial Large and Giant Aneurysms

Acta Neurochirurgica Supplement - Trends in Cerebrovascular Surgery and Interventions ◽

10.1007/978-3-030-63453-7_3 ◽

2021 ◽

pp. 19-26

Author(s):

Matthias Gmeiner ◽

Andreas Gruber

Keyword(s):

Treatment Strategies ◽

High Volume ◽

Mass Effect ◽

Artery Occlusion ◽

Active Management ◽

Definitive Treatment ◽

Parent Artery ◽

Giant Aneurysms ◽

Parent Artery Occlusion ◽

Large And Giant Aneurysms

AbstractIntroduction: Very large and giant aneurysms are among the most challenging cerebrovascular pathologies in neurosurgery.Methods: The aim of this paper is to review the current literature on the management of very large and giant aneurysms and to describe representative cases illustrating possible treatment strategies.Results: In view of the poor natural history, active management using multiprofessional individualized approaches is required to achieve aneurysm occlusion, relief of mass effect, and obliteration of the embolic source. Both reconstructive (clipping, coiling, stent-assisted coiling, flow diversion [FD]) and deconstructive techniques (parent artery occlusion [PAO], PAO in conjunction with bypass surgery, and strategies of flow modification) are available to achieve definitive treatment with acceptable morbidity.Conclusions: Patients harboring such lesions should be managed at high-volume cerebrovascular centers by multidisciplinary teams trained in all techniques of open and endovascular neurosurgery.

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Efficacy of Tocilizumab in Covid 19: A metanalysis of case series studies

10.1101/2020.08.12.20173682 ◽

2020 ◽

Author(s):

shalam Mohamed hussain ◽

Syeda Ayesha Farhana ◽

Osama Alwutayd ◽

Abdullah Alnafeesah ◽

Mohammad Alshammari ◽

...

Keyword(s):

Interleukin 6 ◽

Meta Analysis ◽

Treatment Strategies ◽

Case Series ◽

Standard Of Care ◽

Current Status ◽

Cytokine Storm ◽

Data Synthesis ◽

Quantitative Synthesis ◽

Study Designs

Abstract Background : characteristic feature of COVID-19 during its progression in severity is the cytokine storm (via interleukin-6, IL-6) which is responsible for secondary acute respiratory distress syndrome (ARDS) [4]. Tocilizumab has an antagonist effect on the IL-6 receptor. With present review and metanalysis, we intend to update the current status on the clinical efficacy of tocilizumab in the treatment of Covid 19 infections in the published literature of case series. MATERIALS AND METHODS: The following inclusion criteria were used: (i) case series studies (number of reported patients in each study equal to or greater than ten (ii) use of tocilizumab alone or in combination with standard of care therapy (iii) Covid 19 adult patients (iv) the studies with endpoints on all-cause mortality, need for mechanical ventilation, clinical improvements. Data synthesis and statistical analysis Meta-analysis was performed using a random effects model and the DerSimonian and Laird method. RESULTS 18 were selected for the quantitative analysis (meta-analysis). 14 studies were retrospective and 4 were prospective Meta-analysis The mortality rate of COVID-19 patients with tocilizumab was 21% (251/1212) Asymmetric funnel plot in the cylindrical form due to publication bias In conclusion the present synthesis provide us useful insights with the other available evidence to refine our strategy and equip ourselves effectively with tocilizumab to defeat COVID 19 to save humanity. Limitations The included studies utilized varied doses of tocilizumab (single or double), and duration drug availability issues emerged in some centers, which may have influenced both sample sizes and study designs. Clinical implications: Incorporated studies without control groups into systematic reviews and quantitative synthesis especially when there are no other studies to consider can provide information for formulating effective treatment strategies for management of COVID 19 infections through the use of tocilizumab. Keywords: COVID 19; tocilizumab, interleukin-6, cytokine storm, case series

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Definitive fixation of pelvic and acetabular fractures – current concepts

Chirurgia Narządów Ruchu i Ortopedia Polska ◽

10.31139/chnriop.2020.86.3.3 ◽

2021 ◽

Vol 86 (3) ◽

pp. 80-82

Author(s):

Michał Kułakowski ◽

◽

Paweł Reichert ◽

Karol Elster ◽

Wojciech Piotrowski

Keyword(s):

Pelvic Ring ◽

Damage Control ◽

Treatment Strategies ◽

Mortality Rates ◽

Pelvic Trauma ◽

Definitive Treatment ◽

Acetabular Fractures ◽

Inclusion Criteria ◽

Damage Control Orthopedics ◽

Final Treatment

Introduction. The most challenging injury in orthopedic surgery is pelvic trauma. There are different concepts of treatment strategies, specially in final treatment of pelvic ring and acetabular fractures. Objectives. Analysis of recent studies and evaluation of treatment methods. Materials and Methods. Analysis of 22 recent studies. Five papers met our inclusion criteria, that equated 745 patients. Results. Patients hemodynamically unstable need to be resuscitated and „damage control” orthopedics is widely accepted method. Definitive treatment after fourth day should be performed. Some papers show that early, within 48 hours, definitive treatment of pelvic ring and acetabular fractures give similar or better results. Conclusions. Tendency to early definitive treatment is widely observed and decreases mortality rates and complications.

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