A COST-EFFECTIVE ANALYSIS OF TIOTROPIUM WITH FORMOTEROL AND BUDESONIDE WITH FORMOTEROL BASED ON EFFICACY AND QUALITY OF LIFE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS

Objectives: The primary objective of the study was to conduct the cost-effective analysis of tiotropium with formoterol versus budesonide with formoterol in the management of Stage-I chronic obstructive pulmonary disease (COPD) based on efficacy and quality of life (QoL). The study also aims to analyze the improvement of the QoL through pulmonary rehabilitation. The secondary objective was to evaluate the incidence of depression and anxiety in COPD patients.Methods: A prospective interventional study, with a sample size of 74 patients diagnosed with COPD Stage-I was conducted for 6 months. The study population was divided based on simple randomization into two main groups, one receiving tiotropium with formoterol and the other receiving budesonide with formoterol. Based on spirometry, their pulmonary function test (PFT) was recorded. The patients QoL was recorded using the WHOQoL-BREF questionnaire.Results: Data of 74 patients were collected for both the zero-degree and first-degree follow-up. The patients demonstrated good compliance with the transinhaler of the prescribed drugs. A significant improvement after providing pulmonary rehabilitation in PFT, i.e., forced expiratory volume1/ forced vital capacity values (p=0.000**) and the WHOQoL scoring (P = 0.001**) was observed in patients receiving tiotropium with formoterol. Tiotropium with formoterol was found to be more cost-effective treatment than budesonide with formoterol.Conclusion: The study showed that transinhalation of 9 mcg/12 mcg tiotropium/formoterol once a day is a better cost-effective treatment than 200 mcg/6 mcg transinhalation of budesonide/formoterol twice a day

Design and in vitro study of a dual drug-loaded delivery system produced by electrospinning for the treatment of acute injuries of the central nervous system

Vascular and traumatic injuries of the central nervous system are recognized as global health priorities. A polypharmacology approach that is able to simultaneously target several injury factors by the combination of agents having synergistic effects appears to be promising. Herein, we designed a polymeric delivery system loaded with two drugs, ibuprofen (Ibu) and thyroid hormone triiodothyronine (T3) to in vitro release the suitable amount of the anti-inflammation and the remyelination drug. As a production method, electrospinning technology was used. First, Ibuloaded micro (diameter circa 0.95–1.20 µm) and nano (diameter circa 0.70 µm) fibers were produced using poly(L-lactide) PLLA and PLGA with different lactide/glycolide ratios (50:50, 75:25, and 85:15) to select the most suitable polymer and fiber diameter. Based on the in vitro release results and in-house knowledge, PLLA nanofibers (mean diameter = 580 ± 120 nm) loaded with both Ibu and T3 were then successfully produced by a co-axial electrospinning technique. The in vitro release studies demonstrated that the final Ibu/T3 PLLA system extended the release of both drugs for 14 days, providing the target sustained release. Finally, studies in cell cultures (RAW macrophages and neural stem cell-derived oligodendrocyte precursor cells—OPCs) demonstrated the anti-inflammatory and promyelinating efficacy of the dual drug-loaded delivery platform

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-021-09812-7

Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells

Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown. Therefore, we treated primary PAH patient-derived and healthy pulmonary ECs with BMP9 and observed that stimulation induces transient transcriptional signaling associated with the process of endothelial-to-mesenchymal transition (EndMT). However, solely PAH pulmonary ECs showed signs of a mesenchymal trans-differentiation characterized by a loss of VE-cadherin, induction of transgelin (SM22α), and reorganization of the cytoskeleton. In the PAH cells, a prolonged EndMT signaling was found accompanied by sustained elevation of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling. Herein we identified interleukin-6 (IL6)-dependent signaling to be the central mediator required for the BMP9-induced phenotypic change in PAH pulmonary ECs. Furthermore, we were able to target the BMP9-induced EndMT process by an IL6 capturing antibody that normalized autocrine IL6 levels, prevented mesenchymal transformation, and maintained a functional EC phenotype in PAH pulmonary ECs. In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6

Volume Load-Induced Right Ventricular Failure in Rats Is Not Associated With Myocardial Fibrosis

Background Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction. Methods Wistar rats were subjected to aorto-caval shunt (ACS, n = 23) or sham (control, n = 15) surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed. Results At 6 months, 6/8 ACS-rats (75%) showed clinical signs of RV failure (pleural effusion, ascites and/or liver edema), whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGF beta 1 and pSMAD2/3), or fibrosis were present at any time point. Conclusions In the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model

Structural and cellular mechanisms of peptidyl-prolyl isomerase Pin1-mediated enhancement of Tissue Factor gene expression, protein half-life, and pro-coagulant activity

Therapeutic cell differentiatio

Cellular senescence impairs the reversibility of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH

Zein Coated Zinc Oxide Nanoparticles: Fabrication and Antimicrobial Evaluation as Dental Aid

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Endothelial colony forming cells as an autologous model to study endothelial dysfunction in patients with a bicuspid aortic valve

Bicuspid aortic valve (BAV), the most common congenital heart defect, is associated with an increased prevalence of aortic dilation, aortic rupture and aortic valve calcification. Endothelial cells (ECs) play a major role in vessel wall integrity. Little is known regarding EC function in BAV patients due to lack of patient derive