Bosentan Delivery via Nano Metal-Organic Framework nanoMIL-89 Restores Vascular Homeostasis in Pulmonary Arterial Hypertension

Mashael A Al-Badr,1,2 Hanan H Abunada,1 Richa Gill,3 Hend S Fayed,4 Ayman Al Haj Zen,4 Mohammad A Al-Ghouti,3 Md Mizanur Rahman,2 Nura A Mohamed,1 Haissam Abou-Saleh5 1Biomedical Research Center, QU Health, Qatar University, Doha, Qatar; 2Biological Science Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar; 3Environmental Science Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar; 4College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; 5Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, QatarCorrespondence: Haissam Abou-Saleh, Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar, Email [email protected]: Pulmonary arterial hypertension (PAH) is a progressive vascular disorder characterized by endothelial dysfunction, smooth muscle proliferation, and inflammation. Current treatments, such as Bosentan (an endothelin receptor antagonist), are limited by systemic toxicity and a short half-life. This study aimed to evaluate a nanomedicine formulation of Bosentan using the iron-based metal–organic framework MIL-89 (nanoMIL-89) as a targeted drug delivery platform.Methods: Bosentan-loaded nanoMIL-89 (Bosentan@nanoMIL-89) was synthesized and characterized using microscopy, XRD, FTIR, and HPLC. In vitro assays were conducted on human umbilical vein endothelial cells (HUVECs) and human pulmonary artery smooth muscle cells (HPASMCs) under both basal and lipopolysaccharide (LPS)-induced inflammatory conditions.Results: Bosentan@nanoMIL-89 exhibited no significant cytotoxic or genotoxic effects while maintaining cellular viability. Under basal conditions, it reduced CXCL8 expression by up to 64.38% in HUVECs and 43.34% in HPASMCs. In lipopolysaccharide (LPS)-induced inflammatory conditions, CXCL8 suppression was further enhanced to 94.20% in HUVECs and 58.14% in HPASMCs. In HUVECs, Bosentan@nanoMIL-89 also decreased endothelin-1 (ET-1) release by up to 96.68% and reduced reactive oxygen species (ROS) levels by 46.17% under non-inflammatory conditions. These dose-dependent effects underscore its potent anti-inflammatory and antioxidant properties. Furthermore, Bosentan@nanoMIL-89 promoted angiogenic activity in HUVECs, suggesting therapeutic potential for vascular repair.Conclusion: These findings highlight Bosentan@nanoMIL-89 as a promising nanotherapeutic platform for PAH. By improving efficacy while mitigating systemic side effects, this approach reinforces the broader potential of MOF-based drug delivery systems in the management of vascular diseases. Keywords: nanoparticles, nanomedicine, PAH, endothelial dysfunction, drug delivery, vascular homeostasi

Three-dimensional mapping of cortical bone thickness in subjects with different vertical facial dimensions

Abstract Background The purpose of this study was to determine differences in cortical bone thickness among subjects with different vertical facial dimensions using cone beam computed tomography (CBCT). Methods From 114 pre-treatment CBCT scans, 48 scans were selected to be included in the study. CBCT-synthesized lateral cephalograms were used to categorize subjects into three groups based on their vertical skeletal pattern. Cortical bone thickness (CBT) at two vertical levels (4 and 7 mm) from the alveolar crest were measured in the entire tooth-bearing region in the maxilla and mandible. Results Significant group differences were detected with high-angle subjects having significantly narrower inter-radicular CBT at some sites as compared to average- and low-angle subjects. Conclusions Inter-radicular cortical bone is thinner in high-angle than in average- or low-angle subjects in few selected sites at the vertical height in which mini-implants are commonly inserted for orthodontic anchorage

Age-related change in brain metabolite abnormalities in autism: a meta-analysis of proton magnetic resonance spectroscopy studies

Abnormal trajectory of brain development has been suggested by previous structural magnetic resonance imaging and head circumference findings in autism spectrum disorders (ASDs); however, the neurochemical backgrounds remain unclear. To elucidate neurochemical processes underlying aberrant brain growth in ASD, we conducted a comprehensive literature search and a meta-analysis of 1H-magnetic resonance spectroscopy (1H-MRS) studies in ASD. From the 22 articles identified as satisfying the criteria, means and s.d. of measure of N-acetylaspartate (NAA), creatine, choline-containing compounds, myo-Inositol and glutamate+glutamine in frontal, temporal, parietal, amygdala-hippocampus complex, thalamus and cerebellum were extracted. Random effect model analyses showed significantly lower NAA levels in all the examined brain regions but cerebellum in ASD children compared with typically developed children (n=1295 at the maximum in frontal, P<0.05 Bonferroni-corrected), although there was no significant difference in metabolite levels in adulthood. Meta-regression analysis further revealed that the effect size of lower frontal NAA levels linearly declined with older mean age in ASD (n=844, P<0.05 Bonferroni-corrected). The significance of all frontal NAA findings was preserved after considering between-study heterogeneities (P<0.05 Bonferroni-corrected). This first meta-analysis of 1H-MRS studies in ASD demonstrated robust developmental changes in the degree of abnormality in NAA levels, especially in frontal lobes of ASD. Previously reported larger-than-normal brain size in ASD children and the coincident lower-than-normal NAA levels suggest that early transient brain expansion in ASD is mainly caused by an increase in non-neuron tissues, such as glial cell proliferation

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease