Construction of anti-calcification small-diameter vascular grafts using decellularized extracellular matrix/poly (L-lactide-co-ε-caprolactone) and baicalin-cathepsin S inhibitor

Article

作者: Shi, Ziqi ; Fan, Haojun ; Yang, Jianing ; Zhang, Xiaohai ; Guo, Xiaoqin ; Teng, Yanjiao ; Hou, Shike ; Wang, Shufang ; Lv, Qi ; Ramakrishna, Seeram ; Jiang, Li ; Song, Lin ; Shi, Jie ; Li, Duo

The long-term transplantation of small-diameter vascular grafts (SDVGs) is associated with a risk of calcification, which is a key factor limiting the clinical translation of SDVG. Hence, there is an urgency attached to the development of new SDVGs with anti-calcification properties. Here, we used decellularized extracellular matrix (dECM) and poly (L-lactide-co-ε-caprolactone) (PLCL) as base materials and combined these with baicalin, cathepsin S (Cat S) inhibitor to prepare PBC-SDVGs by electrospinning. Baicalin contains carboxyl and hydroxyl groups that can interact with chemical groups in dECM powder, potentially blocking calcium nucleation sites. Cat S inhibitor prevents elastin degradation and further reduces the risk of calcification. PBC-SDVGs were biocompatible and when implanted in rat abdominal aorta, accelerated endothelialization, enhanced vascular tissue regeneration, inhibited elastin degradation, and promoted macrophage polarization M2 phenotype to regulate inflammation. After 3 months of implantation, the results of Doppler ultrasound, MicroCT, and histological staining revealed a significant reduction in calcification. In summary, the developed anti-calcification SDVGs offer a promising strategy for long-term implantation with significant clinical application potential. STATEMENT OF SIGNIFICANCE: The dECM and PLCL were used as base materials, connected with baicalin, and loaded with Cat S inhibitor to prepare PBC-SDVGs. The baicalin and dECM powder formed hydrogen bonds to crosslink together reducing the calcium deposition. In vitro, the vascular graft downregulated the expression level of osteogenic genes and promoted macrophage polarization toward an anti-inflammatory M2 phenotype, thereby reducing calcification. The PBC-SDVGs implanted in rat abdominal aorta can accelerate endothelialization, enhance vascular tissue regeneration, inhibit elastin degradation, reduce inflammation response and calcification.

2025-01-01·Clinical and Translational Science

A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease

Article

作者: Nagel, Sandra ; Teixeira, Priscila Camillo ; Boyce, Malcolm ; Reis, Bernhard ; Mannino, Marie ; Bentley, Darren ; Manchester, Marianne

AbstractCeliac disease is a chronic, immune‐mediated enteropathy with symptoms triggered by exposure to dietary gluten in genetically predisposed individuals. The only available management option is lifelong adherence to a gluten‐free diet. This randomized, double‐blind, placebo‐controlled, parallel‐group, single‐center study tested the effects of the cathepsin S inhibitor RO5459072 on the immune response to a 13‐day gluten challenge in 19 participants with celiac disease (ClinicalTrials.gov: NCT02679014). Nine participants in the RO5459072 arm received 100 mg study drug b.i.d. (200 mg daily); 10 received a placebo. The primary end point was the number of responders to the gluten challenge (defined as individuals with an increase in the number of gliadin‐specific, IFNγ‐secreting T cells detected using an ELISPOT assay). However, there was a weak response to the gluten challenge across both arms. Few participants had an increase in gliadin‐specific, IFNγ‐secreting T cells, and the antigen‐specific responses (anti‐tTG and anti‐DGP antibodies) were weaker than expected in both arms. Therefore, the primary end point was not met, although the study was underpowered to detect a treatment effect under these circumstances. Pharmacodynamic findings suggested that RO5459072 had some beneficial effects. Fewer participants in the RO5459072 arm exhibited gliadin‐specific IFNγ‐secreting T cells after 6 days' gluten intake. Participants in the RO5459072 arm also showed decreased intestinal permeability, and a decrease in the number of circulating B cells, CD4+ and CD8+ T cells compared to baseline. Nevertheless, the absence of clear effects on the response to a gluten challenge indicates that inhibition of cathepsin S may not be an effective treatment strategy for celiac disease.

2023-11-02·Rheumatology

A randomized, double-blind, placebo-controlled, parallel group study on the effects of a cathepsin S inhibitor in primary Sjögren’s syndrome

Article

作者: Attley, Gemma ; Bentley, Darren ; Fisher, Benjamin A ; Barone, Francesca ; Kolb, Fabrice A

AbstractObjectivesPrimary SS (pSS) is a chronic autoimmune disorder characterized by mucosal dryness and systemic symptoms. We tested the effects of inhibition of cathepsin S using the potent and selective inhibitor RO5459072 on disease activity and symptoms of pSS.MethodsThis was a randomized, double-blind, placebo-controlled, parallel-group, Phase IIA study to investigate the effects of RO5459072 (100 mg twice daily; 200 mg per day). Seventy-five patients with pSS were randomized 1:1 to receive either RO5459072 or placebo for 12 weeks. The primary outcome was the proportion of patients with a ≥3 point reduction from baseline in EULAR SS Disease Activity Index (ESSDAI) score. We also investigated the effects of RO5459072 on quality of life, exocrine gland function, biomarkers related to SS, and safety and tolerability.ResultsThe proportion of patients showing an improvement in ESSDAI score was not significantly different between the RO5459072 and placebo arms. No clinically meaningful treatment effects were observed in favour of RO5459072 for all secondary outcomes. Analysis of soluble biomarkers indicated target engagement between RO5459072 and cathepsin S. There were modest decreases in the number of circulating B cells and T cells in the RO5459072 group, although these did not reach significance. RO5459072 was safe and well-tolerated.ConclusionsThere was no clinically relevant improvement in ESSDAI score (primary endpoint), and no apparent benefit in favour of RO5459072 in any of the secondary clinical endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSS.Trial registrationClinicalTrials.gov; NCT02701985.

100 项与 BF/PC-18 相关的药物交易

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