Activation and contraction of human ‘vascular’ smooth muscle cells grown from circulating blood progenitors

Blood outgrowth smooth muscle cells offer the means to study vascular cells without the requirement for surgery providing opportunities for drug discovery, tissue engineering and personalised medicine. However, little is known about these cells which has meant their therapeutic potential remains unexplored. Our objective was to investigate for the first time the ability of blood outgrowth smooth muscle cells and vessel derived smooth muscle cells to sense the thromboxane mimetic U46619 by measuring intracellular calcium elevation and contraction. U46619 (10 26 -6 M) increased cytosolic calcium in blood outgrowth smooth muscle cells fibroblasts. Increased calcium signal peaked between 10-20 seconds after U46619 in both smooth muscle cell types. Importantly, U46619 (10-9 to 10-6 M) induced concentration-dependent contractions of both blood outgrowth smooth muscle cells and vascular smooth muscle cells but not in fibroblasts. In summary, we show that functional responses of blood outgrowth smooth muscle cells are in line with vascular smooth muscle cells providing critical evidence of their application in biomedical research

Recent Developments in Nanomaterials-Based Drug Delivery and Upgrading Treatment of Cardiovascular Diseases

Cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality worldwide. However, despite the recent developments in the management of CVDs, the early and long outcomes vary considerably in patients, especially with the current challenges facing the detection and treatment of CVDs. This disparity is due to a lack of advanced diagnostic tools and targeted therapies, requiring innovative and alternative methods. Nanotechnology offers the opportunity to use nanomaterials in improving health and controlling diseases. Notably, nanotechnologies have recognized potential applicability in managing chronic diseases in the past few years, especially cancer and CVDs. Of particular interest is the use of nanoparticles as drug carriers to increase the pharmaco-efficacy and safety of conventional therapies. Different strategies have been proposed to use nanoparticles as drug carriers in CVDs; however, controversies regarding the selection of nanomaterials and nanoformulation are slowing their clinical translation. Therefore, this review focuses on nanotechnology for drug delivery and the application of nanomedicine in CVDs

Think like a Virus: Toward Improving Nanovaccine Development against SARS-CoV-2

There is no doubt that infectious diseases present global impact on the economy, society, health, mental state, and even political aspects, causing a long-lasting dent, and the situation will surely worsen if and when the viral spread becomes out of control, as seen during the still ongoing coronavirus disease 2019 (COVID-19) pandemic. Despite the considerable achievements made in viral prevention and treatment, there are still significant challenges that can be overcome through careful understanding of the viral mechanism of action to establish common ground for innovating new preventative and treatment strategies. Viruses can be regarded as devil nanomachines, and one innovative approach to face and stop the spread of viral infections is the development of nanoparticles that can act similar to them as drug/vaccine carriers. Moreover, we can use the properties that different viruses have in designing nanoparticles that reassemble the virus conformational structures but that do not present the detrimental threats to human health that native viruses possess. This review discusses the current preventative strategies (i.e., vaccination) used in facing viral infections and the associated limitations, highlighting the importance of innovating new approaches to face viral infectious diseases and discussing the current nanoapplications in vaccine development and the challenges that still face the nanovaccine field.This research was funded by RC 47/2020 from IRCCS Burlo Garofolo/Italian Ministry of Health and by the QUCG-CAS-22/23-499 Collaborative Grant from Qatar University

Nanomedicine as a Potential Tool against Monkeypox.

Human monkeypox is a rare viral zoonosis that was first identified in 1970; since then, this infectious disease has been marked as endemic in central and western Africa. The disease has always been considered rare and self-limiting; however, recent worldwide reports of several cases suggest otherwise. Especially with monkeypox being recognized as the most important orthopoxvirus infection in humans in the smallpox post-eradication era, its spread across the globe marks a new epidemic. Currently, there is no proven treatment for human monkeypox, and questions about the necessity of developing a vaccine persist. Notably, if we are to take lessons from the COVID-19 pandemic, developing a nanomedicine-based preventative strategy might be prudent, particularly with the rapid growth of the use of nanotechnology and nanomaterials in medical research. Unfortunately, the collected data in this area is limited, dispersed, and often incomplete. Therefore, this review aims to trace all reported nanomedicine approaches made in the monkeypox area and to suggest possible directions that could be further investigated to develop a counteractive strategy against emerging and existing viruses that could diminish this epidemic and prevent it from becoming a potential pandemic, especially with the world still recovering from the COVID-19 pandemic.NAM is a recipient of the Early Career Research Award (ECRA; ECRA03-006-3-004) from the Qatar National Research Fund (QNRF), and the L’Oréal-UNESCO for Women in Science Middle East Regional Young Talents ward 2021. This work was supported by the Ministry of Health, Rome-Italy, in collaboration with the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste–Italy (RC 47/20)

A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a chronicand progressive disease which continues to carry an unacceptablyhigh mortality and morbidity. The nitric oxide (NO) pathwayhas been implicated in the pathophysiology and progressionof the disease. Its extremely short half-life and systemiceffects have hampered the clinical use of NO in PAH. In anattempt to circumvent these major limitations, we have developeda new NO-nanomedicine formulation. The formulationwas based on hydrogel-like polymeric composite NO-releasingnanoparticles (NO-RP). The kinetics of NO release fromthe NO-RP showed a peak at about 120 min followed by asustained release for over 8 h. The NO-RP did not affect theviability or inflammation responses of endothelial cells. TheNO-RP produced concentration-dependent relaxations of pulmonaryarteries in mice with PAH induced by hypoxia. Inconclusion, NO-RP drugs could considerably enhance thetherapeutic potential of NO therapy for PAH

In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity

Impaired adipogenesis is associated with the development of insulin resistance and an increased risk of type 2 diabetes (T2D). GATA Binding Protein 3 (GATA3) is implicated in impaired adipogenesis and the onset of insulin resistance. Therefore, we hypothesize that inhibition of GATA3 could promote adipogenesis, restore healthy fat distribution, and enhance insulin signaling. Primary human preadipocytes were treated with GATA3 inhibitor (DNAzyme hgd40). Cell proliferation, adipogenic capacity, gene expression, and insulin signaling were measured following well-established protocols. BALB/c mice were treated with DNAzyme hgd40 over a period of 2 weeks. Liposomes loaded with DNAzyme hgd40, pioglitazone (positive), or vehicle (negative) controls were administered subcutaneously every 2 days at the right thigh. At the end of the study, adipose tissues were collected and weighed from the site of injection, the opposite side, and the omental depot. Antioxidant enzyme (superoxide dismutase and catalase) activities were assessed in animals’ sera, and gene expression was measured using well-established protocols. In vitro GATA3 inhibition induced the adipogenesis of primary human preadipocytes and enhanced insulin signaling through the reduced expression of p70S6K. In vivo GATA3 inhibition promoted adipogenesis at the site of injection and reduced MCP-1 expression. GATA3 inhibition also reduced omental tissue size and PPARγ expression. These findings suggest that modulating GATA3 expression offers a potential therapeutic benefit by correcting impaired adipogenesis, promoting healthy fat distribution, improving insulin sensitivity, and potentially lowering the risk of T2D.Qatar University H3P grant number QPH3P-BRC-2021-451 (MAE, HN, LM)

Internalization of metal-organic framework nanoparticles in human vascular cells: Implications for cardiovascular disease therapy

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Alteration of endothelial cells and the underlying vasculature plays a central role in the pathogenesis of various CVDs. The application of nanoscale materials such as nanoparticles in biomedicine has opened new horizons in the treatment of CVDs. We have previously shown that the iron metal-organic framework nanoparticle, Materials Institut Lavoisier-89 (nanoMIL-89) represents a viable vehicle for future drug delivery of pulmonary arterial hypertension. In this study, we have assessed the cellular uptake of nanoMIL-89 in pulmonary artery endothelial and smooth muscle cells using microscopy imaging techniques. We also tested the cellular responses to nanoMIL-89 using molecular and cellular assays. Microscopic images showed cellular internalization of nanoMIL-89, packaging into endocytic vesicles, and passing to daughter cells during mitosis. Moreover, nanoMIL-89 showed anti-inflammatory activity without any significant cytotoxicity. Our results indicate that nanoMIL-89 formulation may offer promising therapeutic opportunities and set forth a new prototype for drug delivery not only in CVDs, but also for other diseases yet incurable, such as diabetes and cancer.- The UREP grant [22-140-3-023] from Qatar National Research Fund (QNRF), a member of Qatar Foundation. - The Pickford Award from the British Pharmacological Society (awarded to NAM). - PDRA grants [PDRA3-0324-17001 and PDRA4-0129-18003] from QNRF

A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension

Copyright The Author(s) 2016. This article is published with open access at Springerlink.com. Open Access - This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were madePulmonary arterial hypertension (PAH) is a chronic and progressive disease which continues to carry an unacceptably high mortality and morbidity. The nitric oxide (NO) pathway has been implicated in the pathophysiology and progression of the disease. Its extremely short half-life and systemic effects have hampered the clinical use of NO in PAH. In an attempt to circumvent these major limitations, we have developed a new NO-nanomedicine formulation. The formulation was based on hydrogel-like polymeric composite NO-releasing nanoparticles (NO-RP). The kinetics of NO release from the NO-RP showed a peak at about 120 min followed by a sustained release for over 8 h. The NO-RP did not affect the viability or inflammation responses of endothelial cells. The NO-RP produced concentration-dependent relaxations of pulmonary arteries in mice with PAH induced by hypoxia. In conclusion, NO-RP drugs could considerably enhance the therapeutic potential of NO therapy for PAH.Peer reviewedFinal Published versio

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Assessment of Metal Organic Framework as Potential Drug Carriers in Cardiovascular Diseases

Background: Cardiovascular diseases (CVDs) are considered the major cause of death worldwide. Therapeutic delivery to the cardiovascular system may play an important role in the successful treatment of a variety of CVDs, including atherosclerosis, ischemic-reperfusion injury, and microvascular diseases. Despite their clinical benefits, current therapeutic drugs are hindered by their short half-life and systemic side effects. This limitation could be overcome using controlled drug release with the potential for targeted drug delivery using a nanomedicine approach. In the current study, we have assessed the use of a highly porous nano-sized preparation of iron-based Metal-organic Framework (MOF) commonly referred to as MIL-89 as potential drug carriers in the cardiovascular system. Aims: To assess the effect of MOFs on the viability and cytotoxicity of human vascular cells and the cellular uptake in vitro, and the organ-system toxicity of MOF in vivo using the Zebrafish model. Methods: Human pulmonary endothelial cells (HPAECs) and pulmonary smooth muscle cells (HPASMCs) were treated with variable concentrations of MOFs. The viability, cytotoxicity and anti-inflammatory effects were measured using AlamarBlue, LDH assay and ELISA. The cellular uptake of MOFs were assessed using light, confocal, and transmission electron microscopes and EDS analysis. Moreover, Zebrafish embryos were cultured and treated with MOFs-nanoparticles at 0 hours post fertilization (hpf) followed by different organ-specific assays at 24, 48, and 72 hpf. Results: Although MOFs affect the viability at high concentrations, it does not cause any significant cytotoxicity on HPAECs and HPASMCs. Interestingly, MOFs were shown to have an anti-inflammatory effect. Microscopic images showed an increased (concentration-dependent) cellular uptake of MOFs and transfer to daughter cells in both cell types. Moreover, the in vivo study showed that high concentrations of MOFs delay zebrafish embryos hatching and cause heart deformation, which is currently investigated using cardiotoxicity markers. Conclusion: MOFs is a promising nanoparticle prototypes for drug delivery in the cardiovascular system with high cellular uptake and anti-inflammatory effects. Further investigations of MOFs, including diseased models and drug- loaded formulation is required