Striatal neuronal cell death is one of the pathological features of Huntington's disease (HD). Overexpression of some heat shock proteins (HSPs) has been reported to suppress the aggregate formation of mutant huntingtin and concurrent cell death. Heat shock transcription factor-1 (HSF 1), a major transcription factor of HSPs, has also been reported to be increased in HD models. However, the exact role of HSF 1 in the pathogenesis of HD has not been clearly elucidated. 3-Nitropropionic acid (3NP), an irreversible inhibitor of the mitochondrial complex II, induces selective damage to the striatum in animals and produces clinical features of HD. To investigate roles of HSF 1 on 3NP-induced oxidative stress, HSF 1 was transiently overexpressed in striatal cells. Expression of HSF 1 significantly attenuated 3NP-induced apoptotic striatal cell death and resulted in increased expression of HSP 70. Furthermore, expression of HSF 1 significantly attenuated 3NP-induced intracellular reactive oxygen species (ROS) generation. Taken together, the present study clearly demonstrates that HSF 1 attenuates 3NP-induced apoptotic striatal cell death and ROS generation, possibly through HSP70 expression, suggesting that HSF 1 might be a valuable therapeutic target in the treatment of HD.

Glioblastomas (GBMs) are characterized by four subtypes, proneural (PN), neural, classical, and mesenchymal (MES) GBMs, and they all have distinct activated signaling pathways. Among the subtypes, PN and MES GBMs show mutually exclusive genetic signatures, and the MES phenotype is, in general, believed to be associated with more aggressive features of GBM: tumor recurrence and drug resistance. Therefore, targeting MES GBMs would improve the overall prognosis of patients with fatal tumors. In this study, we propose peroxisome proliferator-activated receptor gamma (PPARγ) as a potential diagnostic and prognostic biomarker as well as therapeutic target for MES GBM; we used multiple approaches to assess PPARγ, including biostatistics analysis and assessment of preclinical studies. First, we found that PPARγ was exclusively expressed in MES glioblastoma stem cells (GSCs), and ligand activation of endogenous PPARγ suppressed cell growth and stemness in MES GSCs. Further in vivo studies involving orthotopic and heterotopic xenograft mouse models confirmed the therapeutic efficacy of targeting PPARγ; compared to control mice, those that received ligand treatment exhibited longer survival as well as decreased tumor burden. Mechanistically, PPARγ activation suppressed proneural–mesenchymal transition (PMT) by inhibiting the STAT3 signaling pathway. Biostatistical analysis using The Cancer Genomics Atlas (TCGA, n = 206) and REMBRANDT (n = 329) revealed that PPARγ upregulation is linked to poor overall survival and disease-free survival of GBM patients. Analysis was performed on prospective (n = 2) and retrospective (n = 6) GBM patient tissues, and we finally confirmed that PPARγ expression was distinctly upregulated in MES GBM. Collectively, this study provides insight into PPARγ as a potential therapeutic target for patients with MES GBM.

Internal pores in calcium phosphate (CaP) scaffolds pose an obstacle in cell seeding efficiency. Previous studies have shown inverse relationships between cell attachment and internal pore size, which mainly resulted from cells flowing to the bottom of culture plates. In order to overcome this structure-based setback, we have designed a method for cell seeding that involves hydrogel. CaP scaffolds fabricated with hydroxyapatite, biphasic calcium phosphate, and β-tricalcium phosphate, had respective porosities of 77.0, 77.9, and 82.5% and pore diameters of 671.1, 694.7, and 842.8 μm. We seeded the cells on the scaffolds using two methods: the first using osteogenic medium and the second using hydrogel to entrap cells. As expected, cell seeding efficiency of the groups with hydrogel ranged from 92.5 to 96.3%, whereas efficiency of the control groups ranged only from 64.2 to 71.8%. Cell proliferation followed a similar trend, which may have further influenced early stages of cell differentiation. We suggest that our method of cell seeding with hydrogel can impact the field of tissue engineering even further with modifications of the materials or the addition of biological factors.

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The molecular mechanism of glioblastoma multiforme (GBM) spread in the brain remains poorly understood. Here, we investigated the mechanism underlying intracranial GBM progression. We found that the mitochondria-derived peptide, humanin, enhances GBM progression via intra-tumoral activation of the integrin alpha V (ITGAV)–TGF beta (TGFβ) signaling axis. In GBM tissues, humanin was significantly upregulated in the tumor area relative to the corresponding normal region. Multiple in vitro pharmacological and genetic approaches revealed that humanin activates the ITGAV pathway, inducing cellular attachment and filopodia formation, aiding the subsequent migration of attached glioblastoma cells via intracellular TGFβR signaling activation. Furthermore, our in vivo orthotopic GBM model supports the pro-tumoral function of humanin, showing a correlation between poor survival and aggressive invasiveness. Tumor protrusions and induced angiogenesis were noted in the humanin-treated group compared with the control. Public databases analysis revealed that genes in the ITGAV–TGFβR axis were significantly associated with poor prognosis in patients with GBM. Collectively, these findings provide evidence of humanin as a pro-tumoral factor, making it a novel biological target for treating GBM.