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Open AccessArticle

Targeted Therapy for Glomerulonephritis Using Arterial Delivery of Encapsulated Etanercept

by Natalia A. Shushunova, Oksana A. Mayorova, Ekaterina S. Prikhozhdenko, Olga A. Goryacheva, Oleg A. Kulikov, Valentina O. Plastun, Olga I. Gusliakova, Albert R. Muslimov, Olga A. Inozemtseva, Nikolay A. Pyataev, Alexander A. Shirokov, Dmitry A. Gorin, Gleb B. Sukhorukov and Olga A. Sindeeva

Int. J. Mol. Sci. 2023, 24(3), 2784; https://doi.org/10.3390/ijms24032784 - 1 Feb 2023

Cited by 6 | Viewed by 3712

Abstract

Complex immunosuppressive therapy is prescribed in medical practice to patients with glomerulonephritis to help them overcome symptoms and prevent chronic renal failure. Such an approach requires long-term systemic administration of strong medications, which causes severe side effects. This work shows the efficiency of polymer capsule accumulation (2.8 ± 0.4 µm) containing labeled etanercept (100 μg per dose) in the kidneys of mice. The comparison of injection into the renal artery and tail vein shows the significant superiority of the intra-arterial administration strategy. The etanercept retention rate of 18% and 8% ID in kidneys was found 1 min and 1 h after injection, respectively. The capsules were predominantly localized in the glomeruli after injection in mice using a model of acute glomerulonephritis. Histological analysis confirmed a significant therapeutic effect only in animals with intra-arterial administration of microcapsules with etanercept. The proposed strategy combines endovascular surgery and the use of polymer microcapsules containing a high molecular weight drug that can be successfully applied to treat a wide range of kidney diseases associated with glomerular pathology. Full article

(This article belongs to the Special Issue Biopolymers in Drug and Gene Delivery Systems 2.0)

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18 pages, 4334 KB

Open AccessArticle

A Synthetic Cell-Penetrating Heparin-Binding Peptide Derived from BMP4 with Anti-Inflammatory and Chondrogenic Functions for the Treatment of Arthritis

by Da Hyeon Choi, Dongwoo Lee, Beom Soo Jo, Kwang-Sook Park, Kyeong Eun Lee, Ju Kwang Choi, Yoon Jeong Park, Jue-Yeon Lee and Yoon Shin Park

Int. J. Mol. Sci. 2020, 21(12), 4251; https://doi.org/10.3390/ijms21124251 - 15 Jun 2020

Cited by 12 | Viewed by 3805

Abstract

We report dual therapeutic effects of a synthetic heparin-binding peptide (HBP) corresponding to residues 15–24 of the heparin binding site in BMP4 in a collagen-induced rheumatic arthritis model (CIA) for the first time. The cell penetrating capacity of HBP led to improved cartilage recovery and anti-inflammatory effects via down-regulation of the iNOS-IFNγ-IL6 signaling pathway in inflamed RAW264.7 cells. Both arthritis and paw swelling scores were significantly improved following HBP injection into CIA model mice. Anti-rheumatic effects were accelerated upon combined treatment with Enbrel^® and HBP. Serum IFNγ and IL6 concentrations were markedly reduced following intraperitoneal HBP injection in CIA mice. The anti-rheumatic effects of HBP in mice were similar to those of Enbrel^®. Furthermore, the combination of Enbrel^® and HBP induced similar anti-rheumatic and anti-inflammatory effects as Enbrel^®. We further investigated the effect of HBP on damaged chondrocytes in CIA mice. Regenerative capacity of HBP was confirmed based on increased expression of chondrocyte biomarker genes, including aggrecan, collagen type II and TNFα, in adult human knee chondrocytes. These findings collectively support the utility of our cell-permeable bifunctional HBP with anti-inflammatory and chondrogenic properties as a potential source of therapeutic agents for degenerative inflammatory diseases. Full article

(This article belongs to the Special Issue Membrane–Peptide Interactions: From Basics to Current Applications)

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19 pages, 623 KB

Open AccessReview

Different Original and Biosimilar TNF Inhibitors Similarly Reduce Joint Destruction in Rheumatoid Arthritis—A Network Meta-Analysis of 36 Randomized Controlled Trials

by Niels Graudal, Benjamin Skov Kaas-Hansen, Louise Guski, Thorbjørn Hubeck-Graudal, Nicky J. Welton and Gesche Jürgens

Int. J. Mol. Sci. 2019, 20(18), 4350; https://doi.org/10.3390/ijms20184350 - 5 Sep 2019

Cited by 20 | Viewed by 5754

Abstract

The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars). Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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16 pages, 3253 KB

Open AccessArticle

Structural and In Vitro Functional Comparability Analysis of Altebrel™, a Proposed Etanercept Biosimilar: Focus on Primary Sequence and Glycosylation

by Ramin Fazel, Yudong Guan, Behrouz Vaziri, Christoph Krisp, Laura Heikaus, Amirhossein Saadati, Siti Nurul Hidayah, Manasi Gaikwad and Hartmut Schlüter

Pharmaceuticals 2019, 12(1), 14; https://doi.org/10.3390/ph12010014 - 17 Jan 2019

Cited by 13 | Viewed by 8050

Abstract

The demand for reliable comparability studies of biosimilars grows with their increased market share. These studies focus on physicochemical, structural, functional and clinical properties to ensure that a biosimilar has no significant differences to the originator product and can be released into the market without extensive clinical trials. In the current study, Enbrel^® (etanercept, the originator) and Altebrel™ (the proposed biosimilar) underwent direct comparison. “Bottom-up” mass spectrometric analysis was used for primary sequence analysis, evaluation of N/O-glycosylation sites and quantification of methionine oxidation. N/O-glycans were analyzed after permethylation derivatization and the effect of N-glycans on in-vitro functionality of etanercept was assayed. Three enzyme peptide mapping resulted in complete identification of the primary structure. It was confirmed that total ion chromatograms are valuable datasets for the analysis of the primary structure of biodrugs. New N/O-glycan structures were identified and all the N-glycans were quantified. Finally, investigation of the functional properties of N-deglycosylated and non-modified etanercept samples using surface plasmon resonance analysis and in-vitro bioassay showed that N-glycosylation has no significant effect on its in-vitro functionality. Analysis of etanercept and its biosimilar, revealed a high similarity in terms of glycosylation, primary structure and in-vitro functionality. Full article

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14 pages, 2606 KB

Open AccessReview

Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis

by Heejin Lim, Sang Hyung Lee, Hyun Tae Lee, Jee Un Lee, Ji Young Son, Woori Shin and Yong-Seok Heo

Int. J. Mol. Sci. 2018, 19(3), 768; https://doi.org/10.3390/ijms19030768 - 7 Mar 2018

Cited by 95 | Viewed by 13561

Abstract

The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel^®), infliximab (Remicade^®), adalimumab (Humira^®), certolizumab-pegol (Cimzia^®), and golimumab (Simponi^®), are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn’s disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFα–TNFα antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFα blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFα. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFα antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFα for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFα plays an important role in pathogenesis. Full article

(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)

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13 pages, 4168 KB

Open AccessArticle

Modulation of Human Airway Barrier Functions during Burkholderia thailandensis and Francisella tularensis Infection

by Cornelia Blume, Jonathan David, Rachel E. Bell, Jay R. Laver, Robert C. Read, Graeme C. Clark, Donna E. Davies and Emily J. Swindle

Pathogens 2016, 5(3), 53; https://doi.org/10.3390/pathogens5030053 - 3 Aug 2016

Cited by 9 | Viewed by 5865

Abstract

The bronchial epithelium provides protection against pathogens from the inhaled environment through the formation of a highly-regulated barrier. In order to understand the pulmonary diseases melioidosis and tularemia caused by Burkholderia thailandensis and Fransicella tularensis, respectively, the barrier function of the human bronchial epithelium were analysed. Polarised 16HBE14o- or differentiated primary human bronchial epithelial cells (BECs) were exposed to increasing multiplicities of infection (MOI) of B. thailandensis or F. tularensis Live Vaccine Strain and barrier responses monitored over 24–72 h. Challenge of polarized BECs with either bacterial species caused an MOI- and time-dependent increase in ionic permeability, disruption of tight junctions, and bacterial passage from the apical to the basolateral compartment. B. thailandensis was found to be more invasive than F. tularensis. Both bacterial species induced an MOI-dependent increase in TNF-α release. An increase in ionic permeability and TNF-α release was induced by B. thailandensis in differentiated BECs. Pretreatment of polarised BECs with the corticosteroid fluticasone propionate reduced bacterial-dependent increases in ionic permeability, bacterial passage, and TNF-α release. TNF blocking antibody Enbrel^® reduced bacterial passage only. BEC barrier properties are disrupted during respiratory bacterial infections and targeting with corticosteroids or anti-TNF compounds may represent a therapeutic option. Full article

(This article belongs to the Special Issue Host Defense Against Bacteria)

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