scholarly journals EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy

2021 ◽  
Vol 22 (20) ◽  
pp. 10945
Author(s):  
Halil I. Ciftci ◽  
Mohamed O. Radwan ◽  
Belgin Sever ◽  
Ahmed K. Hamdy ◽  
Safiye Emirdağ ◽  
...  
Keyword(s):  
In Silico ◽  
Mononuclear Cells ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Antitumor Action ◽  
Central Nervous System Tumor ◽  
Pentacyclic Triterpene ◽  
Peripheral Blood Mononuclear ◽  
Ic50 Value

Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood–brain barrier (BBB).

scholarly journals A New Series of Indeno[1,2-c]pyrazoles as EGFR TK Inhibitors for NSCLC Therapy

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 485
Author(s):  
Ahmet Özdemir ◽  
Halilibrahim Ciftci ◽  
Belgin Sever ◽  
Hiroshi Tateishi ◽  
Masami Otsuka ◽  
...  
Keyword(s):  
In Silico ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Antitumor Agent ◽  
In Vitro Assays ◽  
Antitumor Action ◽  
Peripheral Blood Mononuclear ◽  
Ic50 Value

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC.

scholarly journals Lack of Efficacy of Bevacizumab Plus Irinotecan in Children With Recurrent Malignant Glioma and Diffuse Brainstem Glioma: A Pediatric Brain Tumor Consortium Study

2010 ◽  
Vol 28 (18) ◽  
pp. 3069-3075 ◽  
Author(s):  
Sridharan Gururangan ◽  
Susan N. Chi ◽  
Tina Young Poussaint ◽  
Arzu Onar-Thomas ◽  
Richard J. Gilbertson ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Pediatric Brain Tumor ◽  
Progression Free Survival ◽  
Brainstem Glioma ◽  
Recurrent Malignant Glioma ◽  
Peripheral Blood Mononuclear

Purpose A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG). Patients and Methods Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast–enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ. Results Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure. Conclusion BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.

scholarly journals Leishmania spp Epitopes in Humans Naturally Resistant to the Disease: Working Toward a Synthetic Vaccine

2021 ◽  
Vol 11 ◽  
Author(s):  
Magda Melissa Flórez ◽  
Rocío Rodríguez ◽  
José Antonio Cabrera ◽  
Sara M. Robledo ◽  
Gabriela Delgado
Keyword(s):  
Immune Response ◽  
In Silico ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Clinical Symptoms ◽  
Epitope Prediction ◽  
Effective Vaccine ◽  
Peripheral Blood Mononuclear

Vaccines are one of the most effective strategies to fight infectious diseases. Reverse vaccinology strategies provide tools to perform in silico screening and a rational selection of potential candidates on a large scale before reaching in vitro and in vivo evaluations. Leishmania infection in humans produces clinical symptoms in some individuals, while another part of the population is naturally resistant (asymptomatic course) to the disease, and therefore their immune response controls parasite replication. By the identification of epitopes directly in humans, especially in those resistant to the disease, the probabilities of designing an effective vaccine are higher. The aim of this work was the identification of Leishmania epitopes in resistant humans. To achieve that, 11 peptide sequences (from Leishmania antigenic proteins) were selected using epitope prediction tools, and then, peripheral blood mononuclear cells (PBMCs) were isolated from human volunteers who were previously divided into four clinical groups: susceptible, resistant, exposed and not exposed to the parasite. The induction of inflammatory cytokines and lymphoproliferation was assessed using monocyte-derived dendritic cells (moDCs) as antigen-presenting cells (APCs). The response was evaluated after exposing volunteers’ cells to each peptide. As a result, we learned that STI41 and STI46 peptides induced IL-8 and IL-12 in moDCs and lymphoproliferation and low levels of IL-10 in lymphocytes differentially in resistant volunteers, similar behavior to that observed in those individuals to L. panamensis lysate antigens. We conclude that, in silico analysis allowed for the identification of natural Leishmania epitopes in humans, and also STI41 and STI46 peptides could be epitopes that lead to a cellular immune response directed at parasite control.

scholarly journals Peptides derived from gp43, the most antigenic protein from Paracoccidioides brasiliensis, form amyloid fibrils in vitro: implications for vaccine development

2021 ◽  
Author(s):  
Thyago R Cardim-Pires ◽  
Sant'Anna Ricardo ◽  
Debora Foguel
Keyword(s):  
In Silico ◽  
Mononuclear Cells ◽  
Vaccine Development ◽  
Paracoccidioides Brasiliensis ◽  
Public Health Problem ◽  
Proteinase K ◽  
Important Public Health Problem ◽  
Peripheral Blood Mononuclear ◽  
Potential Vaccine

Fungal infection is an important public health problem afflicting more than a billion people worldwide. Mycoses are especially important in Latin America, and in Brazil in particular. Paracoccidioides is the genus of fungi responsible for paracoccidioidomycosis comprising two species, P. brasiliensis and P. lutzii. The lungs are the primary infection site, but oral mucosa and airways can also be affected. The glycoprotein gp43 is involved in fungi adhesion to epithelial cells and is the most studied protein of P. brasiliensis. Seminal work identified a specific stretch of 15 amino acids that spans the region 181-195 (called P10) as an important epitope of gp43, being recognized by T lymphocytes in peripheral blood mononuclear cells of mice and humans and is envisioned as a potential vaccine component. Here, we show by using thioflavin T (ThT), transmission electron microscopy and other methods that synthetic P10 forms typical amyloid aggregates in solution in very short times, a property that could hamper vaccine development. In silico, aggregation analysis reveals several aggregation-prone regions (APR) in the P10 sequence that are capable of forming amyloid cores with steric zipper architecture. Seeds of P10 obtained by fibril mechanical fragmentation were able to induce the aggregation of P4 but not P23, as evidenced by ThT binding and mass spectrometry. These two peptides, also derived from gp43, are potent modulators of local and systemic inflammation. In-silico proteolysis studies with gp43 revealed that aggregation-prone, P10-like peptides could be generated by the action of several proteases such as proteinase K, trypsin and pepsin, which suggests that P10 could be formed upon gp43 digestion in a physiological condition. Considering our data in the context of a potential vaccine development, we redesigned the sequence of the P10 peptide, maintaining the antigenic region (HTLAIR), but drastically reducing its aggregation propensity.

Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)

2020 ◽  
Author(s):  
Hacer Kuzu Okur ◽  
Koray Yalcin ◽  
Cihan Tastan ◽  
Sevda Demir ◽  
Bulut Yurtsever ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Mononuclear Cells ◽  
Multiple Organ ◽  
Peripheral Blood Mononuclear ◽  
Dornase Alfa ◽  
Tract Infections ◽  
Adult Peripheral Blood

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

scholarly journals Potential Role and Impact of Peripheral Blood Mononuclear Cells in Radiographic Axial Spondyloarthritis-Associated Endothelial Dysfunction

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1037
Author(s):  
Patricia Ruiz-Limon ◽  
Maria L. Ladehesa-Pineda ◽  
Clementina Lopez-Medina ◽  
Chary Lopez-Pedrera ◽  
Maria C. Abalos-Aguilera ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Axial Spondyloarthritis ◽  
Endothelial Injury ◽  
In Vitro Studies ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Endothelial dysfunction (ED) is well known as a process that can lead to atherosclerosis and is frequently presented in radiographic axial spondyloarthritis (r-axSpA) patients. Here, we investigated cellular and molecular mechanisms underlying r-axSpA-related ED, and analyzed the potential effect of peripheral blood mononuclear cells (PBMCs) in promoting endothelial injury in r-axSpA. A total of 30 r-axSpA patients and 32 healthy donors (HDs) were evaluated. The endothelial function, inflammatory and atherogenic profile, and oxidative stress were quantified. In vitro studies were designed to evaluate the effect of PBMCs from r-axSpA patients on aberrant endothelial activation. Compared to HDs, our study found that, associated with ED and the plasma proatherogenic profile present in r-axSpA, PBMCs from these patients displayed a pro-oxidative, proinflammatory, and proatherogenic phenotype, with most molecular changes noticed in lymphocytes. Correlation studies revealed the relationship between this phenotype and the microvascular function. Additional in vitro studies confirmed that PBMCs from r-axSpA patients promoted endothelial injury. Altogether, this study suggests the relevance of r-axSpA itself as a strong and independent cardiovascular risk factor, contributing to a dysfunctional endothelium and atherogenic status by aberrant activation of PBMCs. Lymphocytes could be the main contributors in the development of ED and subsequent atherosclerosis in this pathology.

Differential expression of miRNAs in canine peripheral blood mononuclear cells (PBMC) exposed to Leishmania infantum in vitro

2021 ◽  
Vol 134 ◽  
pp. 58-63
Author(s):  
Matheus Fujimura Soares ◽  
Larissa Martins Melo ◽  
Jaqueline Poleto Bragato ◽  
Amanda de Oliveira Furlan ◽  
Natália Francisco Scaramele ◽  
...  
Keyword(s):  
Differential Expression ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Leishmania Infantum ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Noble Metals for Modern Implant Materials: MOCVD of Film Structures and Cytotoxical, Antibacterial, and Histological Studies

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 851
Author(s):  
Svetlana I. Dorovskikh ◽  
Evgeniia S. Vikulova ◽  
Elena V. Chepeleva ◽  
Maria B. Vasilieva ◽  
Dmitriy A. Nasimov ◽  
...  
Keyword(s):  
Vapor Deposition ◽  
Physical Vapor Deposition ◽  
Noble Metals ◽  
Mononuclear Cells ◽  
Chemical Vapor ◽  
Organic Chemical ◽  
Ti Alloy ◽  
Peripheral Blood Mononuclear ◽  
Histological Studies

This work is aimed at developing the modification of the surface of medical implants with film materials based on noble metals in order to improve their biological characteristics. Gas-phase transportation methods were proposed to obtain such materials. To determine the effect of the material of the bottom layer of heterometallic structures, Ir, Pt, and PtIr coatings with a thickness of 1.4–1.5 μm were deposited by metal–organic chemical vapor deposition (MOCVD) on Ti6Al4V alloy discs. Two types of antibacterial components, namely, gold nanoparticles (AuNPs) and discontinuous Ag coatings, were deposited on the surface of these coatings. AuNPs (11–14 nm) were deposited by a pulsed MOCVD method, while Ag films (35–40 nm in thickness) were obtained by physical vapor deposition (PVD). The cytotoxic (24 h and 48 h, toward peripheral blood mononuclear cells (PBMCs)) and antibacterial (24 h) properties of monophase (Ag, Ir, Pt, and PtIr) and heterophase (Ag/Pt, Ag/Ir, Ag/PtIr, Au/Pt, Au/Ir, and Au/PtIr) film materials deposited on Ti-alloy samples were studied in vitro and compared with those of uncoated Ti-alloy samples. Studies of the cytokine production by PBMCs in response to incubation of the samples for 24 and 48 h and histological studies at 1 and 3 months after subcutaneous implantation in rats were also performed. Despite the comparable thickness of the fibrous capsule after 3 months, a faster completion of the active phase of encapsulation was observed for the coated implants compared to the Ti alloy analogs. For the Ag-containing samples, growth inhibition of S. epidermidis, S. aureus, Str. pyogenes, P. aeruginosa, and Ent. faecium was observed.

Sign in / Sign up

Export Citation Format

Share Document