Search

Brain death (BD) provides most of the donor organs destined for lung transplantation (LTx). However, the organs may be affected by inflammatory and oxidative processes. Based on this, we hypothesize that the angiotensin-converting enzyme 2 (ACE2) activation can reduce the lung injury associated with LTx. 3 h after BD induction, rats were injected with saline (BD group) or an ACE2 activator (ACE2a group; 15 mg/kg -1 ) and kept on mechanical ventilation for additional 3 h. A third group included a control ventilation (Control group) prior to transplant. After BD protocol, left LTx were performed, followed by 2 h-reperfusion. ACE2 activation was associated with better oxygenation after BD management (p = 0.01), attenuating edema (p = 0.05) followed by the reduction in tissue resistance (p = 0.01) and increase of respiratory compliance (p = 0.02). Nrf2 expression was also upregulated in the ACE2a group (p = 0.03). After transplantation, ACE2a group showed lower levels of TNF-α (p = 0.02), IL-6 (p = 0.001), IL-1β (p = 0.01), ROS (p = 0.004) and MDA (p = 0.002), in addition to higher CAT activity (p = 0.04). In conclusion, our study suggests that ACE2 activation improves anti-inflammatory and antioxidant activity in a model of LTx., (© 2024. The Author(s).)

Acquired resistance to drugs that modulate specific protein functions, such as the human proteasome, presents a significant challenge in targeted therapies. This underscores the importance of devising new methodologies to predict drug binding and potential resistance due to specific protein mutations. In this work, we conducted an extensive computational analysis to ascertain the effects of selected mutations (Ala49Thr, Ala50Val, and Cys52Phe) within the active site of the human proteasome. Specifically, we sought to understand how these mutations might disrupt protein function either by altering protein stability or by impeding interactions with a clinical administered drug. Leveraging molecular dynamics simulations and molecular docking calculations, we assessed the effect of these mutations on protein stability and ligand affinity. Notably, our results indicate that the Cys52Phe mutation critically impacts protein-ligand binding, providing valuable insights into potential proteasome inhibitor resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Fernandes, Guedes, Victor, Salvador and Guedes.)

Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC 50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.

Reverse cardiac remodeling may occur in some left ventricular assist device (LVAD) recipients. Although considered the standard therapy, surgical device explantation with repeat sternotomy might be undesirable or very high risk. On the other hand, there are few data reporting minimally invasive percutaneous LVAD deactivation. We describe a case of a man with LVAD malfunction due to driveline fracture and left ventricular (LV) function recovery who had a Heart Mate II deactivated with a percutaneous technique using a left atrial appendage occluder (LAAO) positioned inside the outflow cannula. To the best of our knowledge, this the first report of LVAD deactivation with the fully recapturable LAAO device. We propose that the use of a LAA occluder to obstruct HM II outflow cannula is feasible and safe., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity-a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.

Purpose: Experimental study aimed at evaluating whether pleural neoplastic disease is associated with the degree of pleural fibrosis over time caused by talc pleurodesis. The study describes changes in levels of inflammatory mediators and determines whether the course of time involved in progression of neoplastic pleural disease is the factor that influences safety of talc pleurodesis usage in mice., Materials and Methods: Animals were randomized into two groups: Cancer group (CG) that received intrapleural injection of Lewis cells or Saline group (SG) that received saline injection. After, the animals were subdivided into Early (pleurodesis 3 days after pleural injection) and Late (pleurodesis 7 days after pleural injection) groups. Half of the animals in each group were euthanized 24 hours after pleurodesis (to obtain the inflammatory data); the remaining animals were killed after 8 days (to obtain the scores of pleural fibrosis)., Results: CGs had lower fibrosis scores than SGs comparing early phases to late phases. Inflammation scores were lower in CGs, particularly in Late group. In SGs the inflammation was intense in 100% of the animals. In Late CG group pleural adhesions had the lowest scores; we found intense fibrosis only in SGs. VEGF and LDH levels had increased in animals with cancer, particularly in Late group. Systemic distribution of talc occurred only in Late CG., Conclusions: The time for pleural neoplasia to evolve is inversely proportional to the degree of pleural fibrosis. Earlier pleurodesis yielded the best results related to fibrosis, with less systemic inflammation and is safer in mice., Competing Interests: CONFLICTS OF INTEREST None.

Objectives: Bronchopleural fistula (BPF) is an uncommon complication following a lung resection to address various conditions. BPFs are associated with high morbidity and mortality rates. This study evaluated the endoscopic treatment of 'total' BPFs using the Occlutech-Fígulla® cardiac device at a single centre., Methods: We selected nine patients with chronic and complete BPFs. Under direct bronchoscopic visualization, the BPFs were treated using the Occlutech-Fígulla device. The patients were followed up for 12 months to determine the treatment level and complications., Results: The procedure had a favourable outcome in three patients, resulting in complete fistula closure. Two patients had partial closure and showed improvements in their clinical conditions. In two other cases, closure of the bronchial stump was unsuccessful using this method. Two patients died from causes unrelated to the procedure or the device. During the follow-up period, no complications related to infection or device-related injuries were reported., Conclusions: In patients without clinical conditions that require surgical treatment, the Occlutech-Fígulla cardiac device can be a safe and effective method for the endoscopic treatment of large BPFs resulting from complete dehiscence of a bronchial stump. No severe events were reported., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)