Medicine and Health Sciences Commons^™

Hsp90 Inhibitors Modulate Sars-Cov-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation And Barrier Dysfunction, Ruben Manuel Luciano Colunga Biancatelli, Pavel Solopov, Betsy W. Gregory, Yara Khodour, John D. Catravas

Bioelectrics Publications

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused more than 5 million deaths worldwide. Multiple reports indicate that the endothelium is involved during SARS-Cov-2-related disease (COVID-19). Indeed, COVID-19 patients display increased thrombophilia with arterial and venous embolism and lung microcapillary thrombotic disease as major determinants of deaths. The pathophysiology of endothelial dysfunction in COVID-19 is not completely understood. We have investigated the role of subunit 1 of the SARS-CoV-2 spike protein (S1SP) in eliciting endothelial barrier dysfunction, characterized dose and time relationships, and tested the hypothesis that heat shock protein 90 (HSP90) inhibitors would prevent and repair such injury. S1SP …

Electroporation And Cell Killing By Milli- To Nanosecond Pulses And Avoiding Neuromuscular Stimulation In Cancer Ablation, Emily Gudvangen, Vitalii Kim, Vitalij Novickij, Federico Battista, Andrei G. Pakhomov

Bioelectrics Publications

Ablation therapies aim at eradication of tumors with minimal impact on surrounding healthy tissues. Conventional pulsed electric field (PEF) treatments cause pain and muscle contractions far beyond the ablation area. The ongoing quest is to identify PEF parameters efficient at ablation but not at stimulation. We measured electroporation and cell killing thresholds for 150 ns–1 ms PEF, uni- and bipolar, delivered in 10- to 300-pulse trains at up to 1 MHz rates. Monolayers of murine colon carcinoma cells exposed to PEF were stained with YO-PRO-1 dye to detect electroporation. In 2–4 h, dead cells were labeled with propidium. Electroporation and …

In Vitro And In Vivo Correlation Of Skin And Cellular Responses To Nucleic Acid Delivery, M. Bosnjak, K. Znidar, A. Sales Conniff, T. Jesenko, B. Markelc, Nina Semenova, J. Tur, K. Kohena, S. Kranjc Brezar, L. Heller, M. Cemazar

Bioelectrics Publications

Skin, the largest organ in the body, provides a passive physical barrier against infection and contains elements of the innate and adaptive immune systems. Skin consists of various cells, including keratinocytes, fibroblasts, endothelial cells and immune cells. This diversity of cell types could be important to gene therapies because DNA transfection could elicit different responses in different cell types. Previously, we observed the upregulation and activation of cytosolic DNA sensing pathways in several non-tumor and tumor cell types as well in tumors after the electroporation (electrotransfer) of plasmid DNA (pDNA). Based on this research and the innate immunogenicity of …

The Paradox Of Pulmonary Vascular Resistance: Restoration Of Pulmonary Capillary Recruitment As A Sine Qua Non For True Therapeutic Success In Pulmonary Arterial Hypertension, David Langleben, Stylianos E. Orfanos, Benjamin D. Fox, Nathan Messas, Michele Giovinazzo, John D. Catravas

Bioelectrics Publications

Exercise-induced increases in pulmonary blood flow normally increase pulmonary arterial pressure only minimally, largely due to a reserve of pulmonary capillaries that are available for recruitment to carry the flow. In pulmonary arterial hypertension, due to precapillary arteriolar obstruction, such recruitment is greatly reduced. In exercising pulmonary arterial hypertension patients, pulmonary arterial pressure remains high and may even increase further. Current pulmonary arterial hypertension therapies, acting principally as vasodilators, decrease calculated pulmonary vascular resistance by increasing pulmonary blood flow but have a minimal effect in lowering pulmonary arterial pressure and do not restore significant capillary recruitment. Novel pulmonary arterial hypertension …

Optimizing Antidotal Treatment With The Oral Hsp90 Inhibitor Tas-116 Against Hydrochloric Acid-Induced Pulmonary Fibrosis In Mice, Pavel A. Solopov, Ruben Manuel Luciano Colunga Biancatelli, Christiana Dimitropolou, Tierney Day, John Catravas

Bioelectrics Publications

Exposure to high concentrations of hydrochloric acid (HCl) can lead to severe acute and chronic lung injury. In the aftermath of accidental spills, victims may be treated for the acute symptoms, but the chronic injury is often overlooked. We have developed a mouse model of acute and chronic lung injury, in which the peak of acute lung injury occurs on the day 4 after HCl exposure. We have also demonstrated that HSP90 inhibitors are effective antidotes when administered starting 24 h after HCl. In this study we examined the hypothesis that the novel oral HSP90 inhibitor TAS-116 can effectively ameliorate …

The Heat Shock Protein 90 Inhibitor, At13387, Protects The Alveolo-Capillary Barrier And Prevents Hci-Induced Chronic Lung Injury And Pulmonary Fibrosis, Ruben M.L. Colunga Biancatelli, Pavel Solopov, Christiana Dimitropoulou, Betsy Gregory, Tierney Day, John D. Catravas

Bioelectrics Publications

Hydrochloric acid (HCl) exposure causes asthma-like conditions, reactive airways dysfunction syndrome, and pulmonary fibrosis. Heat Shock Protein 90 (HSP90) is a molecular chaperone that regulates multiple cellular processes. HSP90 inhibitors are undergoing clinical trials for cancer and are also being studied in various pre-clinical settings for their anti-inflammatory and anti-fibrotic effects. Here we investigated the ability of the heat shock protein 90 (HSP90) inhibitor AT13387 to prevent chronic lung injury induced by exposure to HCl in vivo and its protective role in the endothelial barrier in vitro. We instilled C57Bl/6J mice with 0.1N HCl (2 µL/g body weight, intratracheally) and …

Endothelial Cell-Derived Extracellular Vesicles Impair The Angiogenic Response Of Coronary Artery Endothelial Cells, Nigeste Carter, Allison H. Mathiesen, Noel Miller, Michael Brown, Ruben M.L. Colunga Biancatelli, John D. Catravas, Anca D. Dobrian

Bioelectrics Publications

Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair. However, local or distant cues may prevent effective revascularization. Extracellular vesicles (EV) are produced by all cells and endothelium is a rich source of EVs that have access to the main circulation thereby potentially impacting local …

Activation Of Cannabinoid-2 Receptor Protects Against Pseudomonas Aeruginosa Induced Acute Lung Injury And Inflammation, Nagaraja Nagre, Gregory Nicholson, Xiaofei Cong, Janette Lockett, Andrew C. Pearson, Vincent Chan, Woong-Ki Kim, K. Yaragudri Vinod, John D. Catravas

Bioelectrics Publications

Background

Bacterial pneumonia is a major risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pseudomonas aeruginosa (PA), an opportunistic pathogen with an increasing resistance acquired against multiple drugs, is one of the main causative agents of ALI and ARDS in diverse clinical settings. Given the anti-inflammatory role of the cannabinoid-2 receptor (CB2R), the effect of CB2R activation in the regulation of PA-induced ALI and inflammation was tested in a mouse model as an alternative to conventional antibiotic therapy.

Methods

In order to activate CB2R, a selective synthetic agonist, JWH133, was administered intraperitoneally (i.p.) to C57BL/6J …

How To Alleviate Cardiac Injury From Electric Shocks At The Cellular Level, Pamela W. Sowa, Aleksander S. Kiełbik, Andrei G. Pakhomov, Emily Gudvangen, Uma Mangalanathan, Volker Adams, Olga N. Pakhomova

Bioelectrics Publications

Electric shocks, the only effective therapy for ventricular fibrillation, also electroporate cardiac cells and contribute to the high-mortality post-cardiac arrest syndrome. Copolymers such as Poloxamer 188 (P188) are known to preserve the membrane integrity and viability of electroporated cells, but their utility against cardiac injury from cardiopulmonary resuscitation (CPR) remains to be established. We studied the time course of cell killing, mechanisms of cell death, and protection with P188 in AC16 human cardiomyocytes exposed to micro- or nanosecond pulsed electric field (μsPEF and nsPEF) shocks. A 3D printer was customized with an electrode holder to precisely position electrodes orthogonal to …

Alkaline Plasma-Activated Water (Paw) As An Innovative Therapeutic Avenue For Cancer Treatment, Bolun Pang, Zhijie Liu, Sitao Wang, Yuting Gao, Miao Qi, Dehui Xu, Renwu Zhou, Dingxin Liu, Michael G. Kong

Bioelectrics Publications

Plasma-activated water (PAW) is considered to be an effective anticancer agent due to the diverse aqueous reactive oxygen and nitrogen species (RONS: ROS and RNS), but the drawback of low dose and short duration of RONS in acidified PAW limits their clinical application. Herein, this Letter presents an innovative therapeutic avenue for cancer treatment with highly-effective alkaline PAW prepared by air surface plasma. This anticancer alkaline formulation is comprised of a rich mixture of highly chemical RONS and exhibited a prolonged half-life compared to acidified PAW. The H₂O₂, NO₂-, and ONOO^-/O_{2 …}

Atmospheric Air Plasma Streamers Deliver Nanosecond Pulses For Focused Electroporation, Shu Xiao, Carol Zhou, Eric Appia, Shirshak Dhali

Bioelectrics Publications

Background: For electrotherapies that involve electrodes and high-intensity electric fields, such as in tissue ablation, we report a method of pulse delivery that can focus the electric field away from the electrodes, as demonstrated in vitro.

Materials and Methods: To electroporate cells in a monolayer seeded in a 35 mm culture dish, two atmospheric-pressure plasma channels generated by two thin, copper foil electrodes above the surface of the solution provided the current and established the electric field.

Results: Depending on the pulse duration, the plasma channels were observed as corona (100 ns), streamer (300 ns), and mixture of streamer …