Endothelial Cell Damage Research Articles

Sparcl1 and Atherosclerosis.

Atherosclerosis and its complications constitute some of the major diseases affecting humans worldwide. A core component of atherogenesis is endothelial cell damage and dysfunction, which also includes factors such as adhesion and proliferation of various cells. Multiple studies have shown that atherosclerosis and cancer share a common pathophysiological process and exhibit a degree of similarity. Sparcl-1 is a cysteine-rich secretory stromal cell protein present in the extracellular matrix and belongs to the Sparc family of proteins. Its role in tumor development has been widely investigated; however, its role in cardiovascular diseases has rarely been studied. Sparcl-1 is considered an oncogene correlated with the regulation of cell adhesion, migration, and proliferation and is also related to blood vessel integrity. In this review, the potential link between Sparcl-1 and atherosclerosis development is investigated, and recommendations on future research on the role of Sparcl-1 in atherogenesis are provided.

Case report of extranodal natural killer/T-cell lymphoma that induced secondary hemophagocytic syndrome-related histiocytic glomerulopathy

Hemophagocytic syndrome (HPS) is a proliferative disease of the mononuclear macrophage system involving multiple organs and systems. We report a 50-year-old Asian woman who presented with unexplained fever and proteinuria. Laboratory tests showed cytopenia, considerably elevated serum ferritin and IL-2 receptor concentrations, and evidence of hemophagocytosis in the bone marrow. A renal biopsy showed macrophage infiltration into the glomerulus, resulting in podocyte and endothelial cell damage. We finally diagnosed the patient with extranodal natural killer/T-cell lymphoma, nasal type that induced HPS-related histiocytic glomerulopathy. Proteinuria and inflammation responded to treatment with high-dose pulsed methylprednisolone combined with VP-16 and cyclosporine. To the best of our knowledge, this is the first documented case of HPS-related histiocytic glomerulopathy triggered by a malignant tumor.

The activation of histone deacetylases 4 prevented endothelial dysfunction: A crucial mechanism of HuangqiGuizhiWuwu Decoction in improving microcirculation dysfunction in diabetes.

The regulation of epigenetic factors is considered a crucial target for solving complex chronic diseases such as cardio-cerebrovascular diseases. HuangqiGuizhiWuwu Decoction (HGWWD), a classic Chinese prescription, is mainly used to treat various vascular diseases. Although our previous studies reported that HGWWD could effectively prevent vascular dysfunction in diabetic rodent models, the precise mechanism is still elusive. In this study, we investigated the epigenetic mechanisms of modulating the damage of vascular endothelial cells in diabetes by HGWWD. We first analyzed common active components of HGWWD by using HPLC-Q-TOF-MS/MS analysis, and predicted the isoforms of histone deacetylase (HDAC) that can potentially combine the above active components by systems pharmacology. Next, we screened the involvement of specific HDAC isoforms in the protective effect of HGWWD on vascular injury by using pharmacological blockade combined with the evaluation of vascular function in vivo and in vitro. Firstly, HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, SIRT2, and SIRT3 have been implicated with the possibility of binding to the thirty-one common active components in HGWWD. Furthermore, the protective effect of HGWWD is reversed by both TSA (HDAC inhibitor) and MC1568 (class II HDAC inhibitor) on vascular impairment accompanied by reduced aortic HDAC activity in STZ mice. Finally, inhibition of HDAC4 blocked the protective effect of HGWWD on microvascular and endothelial dysfunction in diabetic mice. These results prove the key role of HDAC4 in diabetes-induced microvascular dysfunction and underlying epigenetic mechanisms for the protective effect of HGWWD in diabetes.

Brain-derived extracellular vesicles mediate traumatic brain injury associated multi-organ damage

Traumatic brain injury (TBI) can negatively impact systemic organs, which can lead to more death and disability. However, the mechanism underlying the effect of TBI on systemic organs remains unclear. In previous work, we found that brain-derived extracellular vesicles (BDEVs) released from the injured brain can induce systemic coagulation with a widespread fibrin deposition in the microvasculature of the lungs, kidney, and heart in a mouse model of TBI. In this study, we investigated whether BDEVs can induce heart, lung, liver, and kidney injury in TBI mice. The results of pathological staining and related biomarkers indicated that BDEVs can induce histological damage and systematic dysfunction. In vivo imaging system demonstrated that BDEVs can gather in systemic organs. We also found that BDEVs could induce cell apoptosis in the lung, liver, heart, and kidney. Furthermore, we discovered that BDEVs could cause multi-organ endothelial cell damage. Finally, this secondary multi-organ damage could be relieved by removing circulating BDEVs. Our research provides a novel perspective and potential mechanism of TBI-associated multi-organ damage.

Abstract 655: Protecting The Saphenous Vein Endothelium During Bypass Surgery

Coronary artery bypass graft surgeries commonly use saphenous vein grafts to revascularize diseased coronary arteries. Despite surgical and pharmacological advancements, graft failure rates remain high. Loss of endothelial cells (EC) during saphenous vein harvest and preservation likely contributes to the high incidence of graft failure. Standard methods of saphenous vein preparation and preservation during surgery include perfusion with heparinized saline solutions, a practice known to induce EC damage. As such, improved methods of saphenous vein storage may be the key to preserving EC and reducing graft failure rates. Here, we assessed the hypothesis that maintaining saphenous veins in autologous heparinized blood would preserve EC coverage and reduce cellular damage compared to standard of care, heparinized saline. To investigate this, saphenous vein tissues from 12 patients undergoing coronary artery bypass graft surgery were split into 2 treatment groups, 1) standard maintenance in heparin-saline (n=6) and 2) maintenance in heparin-blood (n=6). At the end of the surgeries, excess saphenous vein tissues were immediately fixed in 4% PFA to analyze endothelial coverage and DNA damage. In heparin-saline veins, histological analysis by H&E and Movat pentachrome staining revealed a broken or absent luminal layer and exposed lamina matrix, suggesting a loss of endothelial cell coverage. Luminal cell coverage was notably increased in heparin-blood samples. Immunofluorescent staining of endothelial markers VE-cadherin and endothelial nitric oxide identified a significant improvement in endothelial coverage in the heparin-blood group compared to heparin-saline. To determine the health of remaining endothelial cells, DNA damage was measured using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Our data show that most of the endothelium (VE-cadherin positive) in heparin-saline tissues was TUNEL positive compared with heparin-blood. In conclusion, our data indicate that maintaining saphenous vein tissues in solutions containing autologous heparinized blood helps preserve the endothelium and maintains vein graft health which has the potential to improve vein graft patency rates in patients.

The Effects of Royal Jelly Samples Collected from Sivas Province on the Proliferation of Endothelial Cells

Honey, bee venom, royal jelly, pollen, propolis and other bee products are natural products that are used to protect and maintain human health, to create a strong and dynamic health condition, and used as a ethnopharmacological medicine in the therapy of some illness. The use of different bee products to strengthen the immune system is still very common today. In this study, it was aimed to determine the in vitro effects of royal jelly samples collected from Sivas province in HUVEC cell culture conditions by determining the healing endothelial damage. In this context, royal jelly samples were obtained from the province of Sivas, where beekeeping is carried out intensively and successfully, in the 2022 harvest period. The effect of royal jelly extracts on the cell proliferation of endothelial cell culture was investigated. Repair of endothelial cell damage, cell growth and development and migration values were measured using the HUVEC cell line, and the data were evaluated with SPSS, GraphPad, ImageJ programs. Although there were significantly important increases in cell growth, development and cell viability values in HUVEC cells treated with different doses of royal jelly at the end of 24 and 48 hours, no statistically significant difference was found in terms of cell migration ratio compared to the control group.

Diosmetin alleviates acute lung injury caused by lipopolysaccharide by targeting barrier function.

Acute lung injury (ALI) is an acute and devastating disease caused by systemic inflammation e.g. patients infected with bacteria and viruses such as SARS-CoV-2 have an unacceptably high mortality rate. It has been well documented that endothelial cell damage and repair play a central role in the pathogenesis of ALI because of its barrier function. Nevertheless, the leading compounds that effectively accelerate endothelial cell repair and improve barrier dysfunction in ALI are largely unknown. In the present study, we found that diosmetin had promising characteristics to inhibit the inflammatory response and accelerate the repair of endothelial cells. Our results indicated that diosmetin accelerated wound healing and barrier repair by improving the expression of the barrier-related proteins, including zonula occludens-l (ZO-1) and occludin, in human umbilical vein endothelial cells (HUVECs) treated with lipopolysaccharide (LPS). Meanwhile, diosmetin administration significantly inhibited inflammatory response by decreasing the content of TNFα and IL-6 in the serum, alleviated lung injury by reducing lung wet/dry (W/D) ratio and histologic score, improved endothelial hyperpermeability by decreasing protein levels and neutrophil infiltration in the bronchoalveolar lavage fluid (BALF) and increasing ZO-1 and occludin expression in the lung tissues of LPS-treated mice. Mechanistically, diosmetin also mediated the expression of Rho A and ROCK1/2 in HUVECs treated with LPS, and fasudil, a Rho A inhibitor remarkably inhibited the role of diosmetin in ZO-1 and occludin proteins. All these findings of this study revealed that diosmetin can be an effective protector of lung injury and the Rho A/ROCK1/2 signal pathway plays a pivotal role in diosmetin accelerating barrier repair in ALI.

Systemic lupus erythematosus with diffuse alveolar hemorrhage.

Systemic lupus erythematosus with diffuse alveolar hemorrhage.

Luteolin ameliorates necroptosis in Glucocorticoid-induced osteonecrosis of the femoral head via RIPK1/RIPK3/MLKL pathway based on network pharmacology analysis

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is deeply relevant to damage and dysfunction of bone microvascular endothelial cells (BMECs). Recently, necroptosis, a newly programmed cell death with necrotic appearance, has garnered increasing attention. Luteolin, a flavonoid compound derived from Rhizoma Drynariae, has numerous pharmacological properties. However, the effect of Luteolin on BMECs in GIONFH through the necroptosis pathway has not been extensively investigated. Based on network pharmacology analysis, 23 genes were identified as potential targets for the therapeutic effect of Luteolin in GIONFH via the necroptosis pathway, with RIPK1, RIPK3, and MLKL being the hub genes. Immunofluorescence staining results revealed high expression of vWF and CD31 in BMECs. In vitro experiments showed that incubation with dexamethasone led to reduced proliferation, migration, angiogenesis ability, and increased necroptosis of BMECs. However, pretreatment with Luteolin attenuated this effect. Based on molecular docking analysis, Luteolin exhibited strong binding affinity with MLKL, RIPK1, and RIPK3. Western blotting was utilized to detect the expression of p-MLKL, MLKL, p-RIPK3, RIPK3, p-RIPK1, and RIPK1. Intervention with dexamethasone resulted in a significant increase in the p-RIPK1/RIPK1 ratio, but the effects of dexamethasone were effectively counteracted by Luteolin. Similar findings were observed for the p-RIPK3/RIPK3 ratio and the p-MLKL/MLKL ratio, as anticipated. Therefore, this study demonstrates that Luteolin can reduce dexamethasone-induced necroptosis in BMECs via the RIPK1/RIPK3/MLKL pathway. These findings provide new insights into the mechanisms underlying the therapeutic effects of Luteolin in GIONFH treatment. Additionally, inhibiting necroptosis could be a promising novel approach for GIONFH therapy.

Kinsenoside alleviates oxidative stress-induced blood-brain barrier dysfunction via promoting Nrf2/HO-1 pathway in ischemic stroke

An ischemic stroke usually causes blood-brain barrier (BBB) damage and excessive oxidative stress (OS) levels. Kinsenoside (KD), a major effective compound extracted in Chinese herbal medicine Anoectochilus roxburghii (Orchidaceae), has anti-OS effects. The present study focused on exploring KD's protection against OS-mediated cerebral endothelial cell damage and BBB damage within the mouse model. Intracerebroventricular administration of KD upon reperfusion after 1 h ischemia decreased infarct volumes, neurological deficit, brain edema, neuronal loss, and apoptosis 72 h post-ischemic stroke. KD improved BBB structure and function, as evidenced by a lower 18F-fluorodeoxyglucose pass rate of the BBB and upregulation of tight junction (TJ) proteins such as occludin, claudin-5, and zonula occludens-1 (ZO-1). KD protected bEnd.3 endothelial cells from oxygen and glucose deprivation/reoxygenation (OGD/R) injury in an in-vitro study. Meanwhile, OGD/R reduced transepithelial electronic resistance, whereas KD significantly increased TJ protein levels. Furthermore, based on in-vivo and in-vitro research, KD alleviated OS in endothelial cells, which is related to nuclear factor, erythroid 2 like 2 (Nrf2) nuclear translocation as well as Nrf2/haem oxygenase 1 signaling protein stimulation. Our findings demonstrated that KD might serve as a potential compound for treating ischemic stroke involving antioxidant mechanisms.

Migration of endothelial cells on the surface of anodized Ni-Ti stent strut.

Stent is widely regarded as the main treatment for curing cardiovascular diseases such as stenosis. Previous research has revealed that the damage of endothelial cells (EC), i.e., the components of endothelium, during stent implantation, could lead to severe complications, such as restenosis. To prevent restenosis, enhancements have been made to surface biocompatibility to accelerate the stent endothelialization process. Anodization on the Ni-Ti is a simple and efficient surface modification method to improve the biocompatibility of the Ni-Ti stent surfaces by enhancing the surface hydrophilicity, leading to an increase in the EC activities. The EC activity is known to be affected by the blood flow. Flow change by stent structure may result in EC dysfunctions, thereby leading to restenosis. It is thus essential to investigate the EC activities resulting from the anodization on the Ni-Ti surface under flow conditions. To study the influence of the endothelialization process on the Ni-Ti stent surface through anodization. The EC attachment and morphology on the anodized stent strut were observed under both with and without the flow conditions. A parallel plate flow chamber was designed to generate a constant wall shear stress (WSS) to study the flow effect on the EC behavior. The hydrophilicity of the Ni-Ti stent strut surface was enhanced by a TiO2 layer fabricated via anodization. The EC distribution on the surface of the anodized nitinol stent strut was observed after 24 h of static (without flow) and flow exposure (with flow) experiment. Under the static condition, the EC density on the surface of the anodized Ni-Ti stent strut was higher compared with the control. Under the flow condition, the enhancement of the EC density on the surface of the stent strut with anodization was reduced. The EC demonstrates a long and thin spindle-shaped morphology under the flow condition. Unlike the static condition, the EC is demonstrating a long and thin morphology in response to the flow under the flow condition. By improving the surface hydrophilicity, the anodization could enhance the EC migration onto the strut surface, and subsequently, accelerate the Ni-Ti stent endothelialization process. The improvement of the surface hydrophilicity is lower under the flow conditions when compared with the static conditions.

A spectrum of novel anti-vascular endothelial cells autoantibodies in idiopathic nephrotic syndrome patients.

Idiopathic nephrotic syndrome (INS) is a common renal disease characterized by disruption of the glomerular filtration barrier. In a previous study, we screened and identified podocyte autoantibodies in nephrotic syndrome patients and proposed the concept of autoimmune podocytopathy. However, circulating podocyte autoantibodies cannot reach podocytes unless glomerular endothelial cells have been damaged. Therefore, we speculate that INS patients may also have autoantibodies against vascular endothelial cells. Sera from INS patients were used as primary antibodies to screen and identify endothelial autoantibodies by hybridization with vascular endothelial cell proteins separated by two-dimensional electrophoresis. The clinical application value and pathogenicity of these autoantibodies were further verified by clinical study and in vivo and in vitro experiments. Nine kinds of autoantibodies against vascular endothelial cells were screened in patients with INS, which can cause endothelial cell damage. In addition, 89% of these patients were positive for at least one autoantibody.

L-ascorbic acid could ameliorate the damage of myocardial microvascular endothelial cell caused by hypoxia-reoxygenation via targeting HMGB1

In this study, we intend to explore the potential function of l-ascorbic acid in hypoxia-reoxygenation (H/R)-induced damage of CMECs and its related molecular mechanism. With different concentrations of l-ascorbic acid treatment, the proliferation, migration, inflammation and autophagy of cardiac microvascular endothelial cells (CMECs) were determined by several biological experiments. Si-HMGB1 transfection was used to reduce HMGB1 expression and to detect the function of HMGB1 in H/R-induced damage of CMECs. Under H/R condition, the proliferation and migration abilities of CMECs were reduced, and the inflammation and autophagy of CMECs were increased. Whereas, after l-ascorbic acid treatment, the reduction in the proliferation and migration of CMECs, as well as the increase in the inflammation and autophagy of CMECs induced by H/R were reversely altered. HMGB1 was confirmed as a specific target of l-ascorbic acid, and si-HMGB1 treatment strengthened the beneficial effect of l-ascorbic acid on H/R-induced damage of CMECs, followed by further reduction in the proliferation and migration abilities of CMECs, as well as the increase in the inflammation and autophagy of CMECs. Few studies have reported the function of l-ascorbic acid in myocardial ischemia on CMECs, but our experimental data showed that l-ascorbic acid treatment could ameliorate the H/R-induced damage of CMECs by regulating HMGB1 expression.

552 Quantifying the Blood-Brain Barrier in Acute Ischemic Stroke Using Novel MR Imaging

INTRODUCTION: Acute ischemic stroke causes endothelial cell and tight junction damage, resulting in blood-brain barrier (BBB) disruption. BBB disruption is a significant risk factor for hemorrhagic conversion, which is seen in up to 20-40% of patients, increasing mortality by 7.9-fold. A number of processes, such as reperfusion injury, neuroinflammation, and neoangiogenesis impact the BBB permeability, which can fluctuate for several weeks after stroke. Despite its significance, BBB permeability is not taken into consideration in the management of this patient population. METHODS: We used two MRI sequences, diffusion-prepared pseudocontinuous arterial spin labeling (DP-pCASL) and Neurite Orientation Dispersion and Density Imaging (NODDI) to scan patients greater than 18 years old who presented with acute ischemic stroke. DP-pCASL generates cerebral blood flow, arterial transit time (ATT), and BBB permeability. NODDI generates neurite dispersion index (NDI), orientation dispersion index (ODI), and free water index (ISO) maps. Normalized BBB permeability above the 75th percentile of the vascular territories was defined as high permeability. RESULTS: Ten patients were enrolled with a mean age of 66.8 ± 13.9 and NIHSS of 15.8 ± 8.0. Patients were scanned at a mean 83.4 ± 78.8 hours from symptom onset. Two patients had received alteplase and 6 patients underwent mechanical thrombectomy. Multivariable logistic regression showed that increasing ATT (p <0.001), decreasing ODI signal (p = 0.001), increasing relative monocyte count (p = 0.001) were significant predictors of increased BBB permeability. Intubation/general anesthesia decreased the odds of high BBB permeability (OR 0.072, p < 0.001). CONCLUSIONS: Higher ATT, higher monocyte count, lower ODI, and lack of anesthesia were significant predictors of high BBB permeability in stroke patients. We provide a detailed account of our addition of DP-pCASL and NODDI into the stroke imaging protocol.

5610845 A PHASE 1 STUDY OF CSL888 (HEMOPEXIN) IN ADULT PATIENTS WITH SICKLE CELL DISEASE

Background: Episodes of vaso-occlusive crisis (VOC) are the primary reason for hospitalization among patients with sickle cell disease (SCD). The release of heme from the breakdown of damaged red blood cells is thought to play an important role in contributing to vaso-occlusion in SCD. Free heme promotes activation of endothelium, expression of endothelial cell adhesion molecules and activation of blood cells (neutrophils, monocytes, and platelets) which “stick” to the blood vessel walls. The net result is blockage of blood circulation, resulting in the characteristic pain of VOC. Hemopexin is a 60 kilodalton (kDa) plasma glycoprotein that is mainly expressed in the liver and belongs to the family of acute-phase proteins whose synthesis is induced after an inflammatory event. Hemopexin binds extracellular heme with the highest known affinity (KD < 1pM) of all plasma proteins. In patients with SCD, hemopexin levels are significantly reduced (approximately 85%) compared to healthy controls due to increased consumption. CSL889 is human plasma-derived hemopexin. It is hypothesized that pharmacological administration of CSL889 may decrease heme toxicity, restore normal blood circulation and therefore have beneficial effects in the management of acute VOC in SCD patients. Translation to the clinic is supported by studies performed in vitro demonstrating protection of heme-mediated endothelial cell damage and in vivo using the Townes mouse model of SCD, in which hemopexin was shown ameliorate vaso-occlusion following hemoglobin or hypoxia/reperfusion challenges (Gentinetta et al. 2022). Preclinical repeat dose toxicity studies in animals have evidenced favorable tolerability up to the highest dose level tested. Methods: We describe the design of a Phase 1, first in human, multicenter, open-label study to evaluate the safety, tolerability, and pharmacokinetics (PK) of CSL889 in adult patients with SCD following single intravenous (IV) doses of CSL889 [NCT04285827]. The study will comprise 2 parts. Part A will include patients with SCD in their usual health (not in VOC) who will receive a single dose of CSL889 at one of up to 6 different dose levels. In Part B, patients with SCD who present in VOC requiring intravenous (IV) opioid injections and admission to hospital for further management, will receive a single dose of CSL889 at a level that has been shown to be safe and tolerable in Part A within 36 hours of in-patient admission. All subjects will be followed up for 32 days post-infusion of CSL889. The range of doses to be studied is based on a translational PK model based on data derived from the study of CSL889 in the Townes mouse model of SCD. Results: The primary objective is to determine the safety and tolerability of single doses of CSL889 given to patients with SCD both without (Part A) and with (Part B) active VOC. The secondary objectives are to determine the PK and immunogenicity of CSL889. Exploratory objectives are to determine changes in biomarkers of target engagement (including changes in cell-free heme) and pharmacodynamic biomarkers related to the mechanism of action. Change in pain scores (as measured by Numeric Rating Scale [NRS]) will be additionally evaluated in Part B. Conclusions: Enrollment is in progress. No serious adverse events considered related to the administration of CSL889 have been reported as of 01-Sep-2022. Disclosures: F Wilson, J Jochems, L Lindqvist, K Jung,T Gentinetta, S Costin and GJ Kato are employed by CSL Reference 1. Gentinetta et al, J Clin Med 2022, 11:630

ATYPICAL HEMOLYTIC UREMIC SYNDROME: A CASE STUDY

Atypical hemolytic uremic syndrome (aHUS) is a systemic disease, a type of thrombotic microangiopathy (TMA). It is based on uncontrolled activation of the alternative complement pathway of a hereditary or acquired nature, leading to generalized thrombosis in the microvasculature. Chronic activation of the alternative complement pathway leads to the damage of endothelial cells, erythrocytes and platelets and, as a result, to thrombotic microangiopathy and systemic multiorgan damage. Currently, in roughly half of the cases, it is impossible to identify aHUS triggers. Fresh frozen plasma (FFP) is used as first-line drug to reverse the symptoms. It helps to eliminate the deficiency of self-proteins – complement factor H and complement factor I (CFH and CFI), membrane cofactor protein (MCP), and stable and labile proteins – factors of hemostasis, and to stop thrombosis in the microvasculature. FFP administration is a preparatory step before anticomplementary therapy. Disease prognosis is always serious and is associated with severe complications and high mortality. At least 6 % of patients develop multiple organ failure with generalized TMA, injury of the central nervous system, gastrointestinal tract, lungs, and kidneys. The paper describes a clinical case of a patient with aHUS.

The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review.

Immunothrombosis has emerged as a dominant pathological process exacerbating morbidity and mortality in acute- and long-COVID-19 infections. The hypercoagulable state is due in part to immune system dysregulation, inflammation and endothelial cell damage, as well as a reduction in defense systems. One defense mechanism in particular is glutathione (GSH), a ubiquitously found antioxidant. Evidence suggests that reduction in GSH increases viral replication, pro-inflammatory cytokine release, and thrombosis, as well as decreases macrophage-mediated fibrin removal. The collection of adverse effects as a result of GSH depletion in states like COVID-19 suggest that GSH depletion is a dominant mechanism of immunothrombosis cascade. We aim to review the current literature on the influence of GSH on COVID-19 immunothrombosis pathogenesis, as well as the beneficial effects of GSH as a novel therapeutic for acute- and long-COVID-19.

MR-guided ultrasound-stimulated microbubble therapy enhances radiation-induced tumor response

High intensity focused ultrasound (HIFU) systems have been approved for therapeutic ultrasound delivery to cause tissue ablation or induced hyperthermia. Microbubble agents have also been used in combination with sonication exposures. These require temperature feedback and monitoring to prevent unstable cavitation and prevent excess tissue heating. Previous work has utilized lower power and pressure to oscillate microbubbles and transfer energy to endothelial cells in the absence of thermally induced damage that can radiosensitize tumors. This work investigated whether reduced acoustic power and pressure on a commercial available MR-integrated HIFU system could result in enhanced radiation-induced tumor response after exposure to ultrasound-stimulated microbubbles (USMB) therapy. A commercially available MR-integrated HIFU system was used with a hyperthermia system calibration provided by the manufacturer. The ultrasound transducer was calibrated to reach a peak negative pressure of − 750 kPa. Thirty male New Zealand white rabbits bearing human derived PC3 tumors were grouped to receive no treatment, 14 min of USMB, 8 Gy of radiation in a separate irradiation cabinet, or combined treatments. In vivo temperature changes were collected using MR thermometry at the tumor center and far-field muscle region. Tissues specimens were collected 24 h post radiation therapy. Tumor cell death was measured and compared to untreated controls through hematoxylin and eosin staining and immunohistochemical analysis. The desired peak negative pressure of − 750 kPa used for previous USMB occurred at approximately an input power of 5 W. Temperature changes were limited to under 4 °C in ten of twelve rabbits monitored. The median temperature in the far-field muscle region of the leg was 2.50 °C for groups receiving USMB alone or in combination with radiation. Finally, statistically significant tumor cell death was demonstrated using immunohistochemical analysis in the combined therapy group compared to untreated controls. A commercial MR-guided therapy HIFU system was able to effectively treat PC3 tumors in a rabbit model using USMB therapy in combination with radiation exposures. Future work could find the use of reduced power and pressure levels in a commercial MR-guided therapy system to mechanically stimulate microbubbles and damage endothelial cells without requiring high thermal doses to elicit an antitumor response.

Mechanisms of COVID-19 Associated Pulmonary Thrombosis: A Narrative Review.

COVID-19, the infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is frequently associated with pulmonary thrombotic events, especially in hospitalized patients. Severe SARS-CoV-2 infection is characterized by a proinflammatory state and an associated disbalance in hemostasis. Immune pathology analysis supports the inflammatory nature of pulmonary arterial thrombi composed of white blood cells, especially neutrophils, CD3+ and CD20+ lymphocytes, fibrin, red blood cells, and platelets. Immune cells, cytokines, chemokines, and the complement system are key drivers of immunothrombosis, as they induce the damage of endothelial cells and initiate proinflammatory and procoagulant positive feedback loops. Neutrophil extracellular traps induced by COVID-19-associated "cytokine storm", platelets, red blood cells, and coagulation pathways close the inflammation-endotheliopathy-thrombosis axis, contributing to SARS-CoV-2-associated pulmonary thrombotic events. The hypothesis of immunothrombosis is also supported by the minor role of venous thromboembolism with chest CT imaging data showing peripheral blood clots associated with inflammatory lesions and the high incidence of thrombotic events despite routine thromboprophylaxis. Understanding the complex mechanisms behind COVID-19-induced pulmonary thrombosis will lead to future combination therapies for hospitalized patients with severe disease that would target the crossroads of inflammatory and coagulation pathways.

Assessment of Biocompatibility of 3D‐Printed Cardiovascular Stent

AbstractThis study aims to evaluate the biocompatibility of the 3D‐printed stent and its efficiency on reducing the oxidized‐low‐density lipoprotein (ox‐LDL) damage in endothelial cells using the zebrafish embryos model. The human umbilical vein endothelial cells (HUVECs) significantly (p‐value &lt;0.001) lose their viability upon exposure to ox‐LDL treatment (100 µg/ml). An exposure of HUVECs to resveratrol (RSL)‐unloaded 3D stent slightly lowers the cell viability as compared with untreated control group. On the contrary, RSL‐loaded 3D stent exposure groups maintain initial cell viability. The amounts of TNF‐α and IL‐β released from zebrafish embryos (1.82 ± 0.75 and 1.87 ± 0.24) in the group treated with the RSL‐loaded 3D stents are significantly lower (p &lt; 0.001) than those from the LPS alone treated group (8.13 ± 2.29 and 23.79 ± 3.82, respectively). It is found that RSL‐loaded 3D stent at a RSL dose of 1 mm shows no mortality during the developmental stages, but RSL‐loaded 3D stent at a dose of 2 mm shows a lowered survival rate (93.3 ± 3.3%), shorter length of larvae, pericardial and yolk sac edemas of 53.3 ± 23.3% and 3.3 ± 3.3%, respectively. The RSL‐loaded 3D stents efficiently downregulate the proinflammatory cytokines, and protect an organism against oxidative stress, while producing minimal developments defects in zebrafish embryos.