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Nanoparticles for Cardiovascular Medicine: Trends in Myocardial Infarction Therapy
Published in Harishkumar Madhyastha, Durgesh Nandini Chauhan, Nanopharmaceuticals in Regenerative Medicine, 2022
Growth factors such as VEGF and FGF1 have established roles in promoting angiogenesis, which following MI injury, is a critical step in realizing cardiac repair and recover of functional ability. Oduk et al. described the use of PLGA nanoparticles for the loading and delivery of VEGF for restoration of post-MI vascularisation (Oduk et al. 2018). VEGF release was continuous for over 30 days following injection into the peri-infarct region of heart tissue in mouse models of MI. This sustained release improved cardiac function over the course of four weeks posttreatment, largely due to the gradual biodegradation of PLGA, controlled release of VEGF and subsequent enhanced angiogenesis in the infarct site. Fan et al. combined cytokine therapy with co-delivery of a Wnt1 agonist/GSK-3β antagonist, CHIR99021 (Fan et al. 2020b). Following encapsulation of both therapeutics into PLGA nanoparticles, the researchers found that slow release over 4 weeks had a synergistic effect on the enhancement of cardiomyocyte growth and proliferation in vitro. Intramyocardial injection of the nanoparticles protected the myocardium against MI injury and reduced the infarct size in both mouse and pig models of post-MI left ventricular remodelling. In addition, cardiac contractile function was maintained, cardiomyocyte apoptosis was reduced, and an increased rate of angiogenesis was observed.
“Kidney in a Dish” Organoids for PKD
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Nelly M. Cruz, Benjamin S. Freedman
The first techniques to differentiate human pluripotent stem cells (hPSC) stepwise into kidney organoids have recently been established.8,12–14 hPSC include both human embryonic stem (ES) cells, which are cultured from blastocyst-stage embryos, and human induced pluripotent stem (iPS) cells, which are reprogrammed from somatic cells.15,16 CHIR99021, a small molecule inhibitor of GSK3β and related kinases, is typically applied to hPSC to induce differentiation into the renal lineage. Differentiation from hPSC to kidney organoid typically takes approximately 3 weeks. A variety of different culture geometries are possible, ranging from adherent cultures similar to a typical monolayer, to spheroid aggregates of dissociated cells. Side-by-side comparisons of organoid differentiation protocols demonstrate that the cell types that emerge in these systems are similar regardless of the particular reagents or geometry used.10,11,17,18
Involvement of β-catenin in Androgen-induced Mesenchymal Transition of Breast MDA-MB-453 Cancer Cells
Published in Endocrine Research, 2021
Mamoun Ahram, Randa Bawadi, Mohammad S. Abdullah, Dana B. Alsafadi, Haneen Abaza, Sallam Abdallah, Ebtihal Mustafa
GSK-3β stimulates the degradation of β-catenin and its inhibition promotes β-catenin-mediated signaling. The possible connection between β-catenin signaling and AR in the mesenchymal transition of MDA-MB-453 cells and the role of AR, if any, in modulating this effect in MDA-MB-453 cells were investigated further. Cells were treated for 72 hrs with 10 µM of CHIR99021, a synthetic compound that blocks GSK-3β activity. The functional effectiveness of this inhibitor at the applied concentration (i.e. 10 µM) in these cells was shown in a previous study.44 Relative to the epithelial morphology of vehicle-treated cells (Figure 7A), inhibition of GSK-3β induced mesenchymal transformation of MDA-MB-453 cells in the absence of DHT (Figure 7B). Exposing cells to both CHIR99021 and DHT increased the proportion of cells with a mesenchymal phenotype and elongated the cells further (Figure 7C). Interestingly, the addition of bicalutamide to cells treated with the GSK-3β inhibitor in the absence of DHT completely blocked their mesenchymal transformation (Figure 7D). The latter cells also possessed thick actin filaments with pronounced focal adhesions. Additional images are presented in Figure 1S. These results suggest that not only β-catenin may be critical in DHT-induced EMT, but AR could also be reciprocally important in the β-catenin-induced mesenchymal transformation of cells even in the absence of AR agonist.
Experimental drugs for the prevention or treatment of sensorineural hearing loss
Published in Expert Opinion on Investigational Drugs, 2023
Judith S Kempfle, David H. Jung
This concept has been the basis of clinical trials with FX-322, a combinatorial preparation of CHIR99021 and VPA aiming to induce hair cell regeneration from supporting cells after local intratympanic application. The initial data from a Phase Ib clinical trial in subjects with moderate-to-severe SNHL was recently published [108]. Stable improvement was documented for speech discrimination scores in a subpopulation of subjects with preexisting reduced word recognition scores after one injection of FX-322, although pure tone thresholds did not change significantly in this small group of 15 subjects. A positive trend at the extended high frequencies (at and above 8 kHz) was noted, however. Additional follow-up trials, which included single and multiple applications of FX-322, demonstrated a trend toward improved speech discrimination, but no significant difference in threshold audiograms. The lack of improvement of pure tone thresholds begs the question as to whether the claimed hair cell regeneration is in fact taking place in humans after FX-322 treatment. Based on the published PK data, the drug may only be present in therapeutic concentrations at the extended high frequency (EHF) range of around 8 kHz but may not reach lower frequencies at sufficient levels. This may be relevant, as others have theorized that EHFs may be responsible for impaired hearing in noise in patients with normal threshold audiograms [109]. Additional studies are needed to determine if the improvement in word recognition could be related to ongoing synaptic regenerative processes. Table 2 summarizes clinical trials for inner ear regeneration.
Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2016–2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Carlos Roca, Nuria E. Campillo
GSK-3 is overexpressed and hyperactivated in nonsmall cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. O’Flaherty et al. studied the effects of a GSK3 inhibitor named CHIR99021 (alone or in combination with paclitaxel, also called taxol, used to treat various cancer), using an in vitro cell growth assay and a tumor xenograft model. CHIR99021 (Figure 5) inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. The findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer [66].