👤 Hisaka Kurita

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron cell death. A GGGGCC hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is a major causative factor in ALS. This abnormal HRE triggers five types of dipeptide repeat protein (DPR), each composed of two alternating amino acid expressions. Among the DPRs, arginine-rich Poly-PR localizes predominantly to the nucleus, exerting particularly strong toxicity on motor and cortical neurons. Several mechanisms have been proposed for poly-PR-induced neurotoxicity. In this study, poly-PR-expressing NSC34 motor neuron-like cells showed an increase in oxidative stress. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. However, its neuroprotective effects against DPR-induced toxicity have not been previously reported. Here, we demonstrated that FGFR1 activation reduced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) expression. Furthermore, we propose that the increase in NRF2 through FGFR1 activation may result from the alleviation of protein translation impairment. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity and may represent a potential therapeutic strategy for ALS. Show less

A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. Nevertheless, there has been no previous report of its neuroprotective effects against poly-PR toxicity. The objective of this study was to investigate the neuroprotective effects of FGFR1 activation in poly-PR-expressing NSC34 motor neuron-like cells. RT-qPCR analysis in NSC34 cells showed that Fgfr1 was the most highly expressed member of the Fgfr family in NSC34 cells. The activation of FGFR1 by FGF2, a common ligand for all FGFRs, exerted neuroprotective effects against the toxicity of poly-PR. Additionally, FGFR1 activation was observed to enhance cell viability through the PI3K-AKT pathway, while the contribution of the MEK-ERK pathway was found to be limited. Furthermore, FGFR1 activation suppressed the accumulation of p53 protein and promoted its degradation through increased murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets p53. The neuroprotective effects were attenuated by PD173074, a selective FGFR1 inhibitor or Nutlin-3a, an inhibitor of the p53-MDM2 interaction. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity. Consequently, this study suggests the potential utility of FGFR1 activation as a therapeutic strategy for ALS. Show less

A 64-year-old man was diagnosed with diffuse large B-cell lymphoma (DLBCL). He achieved complete remission after R-CHOP therapy, but experienced relapse as lymphoplasmacytic lymphoma (LPL) 4 years after initial treatment. He was retreated with R-bendamustine therapy, resulting in a second remission. However, he once again experienced relapse as DLBCL 2 years later. Although lymph node lesions disappeared after salvage chemotherapy, facial and hypoglossal nerve paresis due to tumor infiltration appeared. His symptoms were attributed to cranial nerve invasion of transformed LPL, and treatment with tirabrutinib was started. Neurological symptoms markedly improved and high-dose chemotherapy followed by autologous stem cell transplantation was performed, resulting in long-term remission. Mutational analyses suggested that a B cell clone with MYD88 mutation caused the entire course of the disease, and our experience with this case indicates that Bruton's tyrosine kinase (BTK) inhibitor therapy might be effective for such cases. Show less

Metformin, an AMP-activated protein kinase activator used to treat diabetes mellitus, has recently attracted attention as a promising anti-fibrotic agent. However, its anti-fibrotic effects on pleural fibroelastosis remain unknown. We induced mouse pleural fibroelastosis by intra-pleural coadministration of bleomycin and carbon and evaluated its validity as a preclinical model for human pleural fibrosis. We assessed the expression of the myofibroblast surface marker CD90 in the fibrotic pleura and the effects of metformin Show less

Special AT-rich sequence binding protein 2 (SATB2) is an evolutionarily conserved transcription factor that has multiple roles in neuronal development, osteoblast differentiation, and craniofacial patterning. SATB2 binds to the nuclear matrix attachment region, and regulates the expression of diverse sets of genes by altering chromatin structure. Recent studies have reported that high expression of SATB2 is associated with favorable prognosis in colorectal and laryngeal cancer; however, it remains uncertain whether SATB2 has tumor-suppressive functions in cancer cells. In this study, we examined the effects of SATB2 expression on the malignant characteristics of colorectal cancer cells. Expression of SATB2 repressed the proliferation of cancer cells in vitro and in vivo, and also suppressed their migration and invasion. Extracellular signal-regulated kinase 5 (ERK5) is a mitogen-activated protein kinase that is associated with an aggressive phenotype in various types of cancer. SATB2 expression reduced the activity of ERK5, and constitutive activation of ERK5 restored the proliferation, anchorage-independent growth, migration and invasion of SATB2-expressing cells. Our results demonstrate the existence of a novel regulatory mechanism of SATB2-mediated tumor suppression via ERK5 inactivation. Show less

Tight junctions (TJs) and adherens junctions (AJs) form an apical junctional complex at the apical side of the lateral membranes of epithelial cells, in which TJs are aligned at the apical side of AJs. Many cell adhesion molecules (CAMs) and cell polarity molecules (CPMs) cooperatively regulate the formation of the apical junctional complex, but the mechanism for the alignment of TJs at the apical side of AJs is not fully understood. We developed a cellular system with which epithelial-like TJs and AJs were reconstituted in fibroblasts and analyzed the cooperative roles of CAMs and CPMs. We exogenously expressed various combinations of CAMs and CPMs in fibroblasts that express negligible amounts of these molecules endogenously. In these cells, the nectin-based cell-cell adhesion was formed at the apical side of the junctional adhesion molecule (JAM)-based cell-cell adhesion, and cadherin and claudin were recruited to the nectin-3- and JAM-based cell-cell adhesion sites to form AJ-like and TJ-like domains, respectively. This inversed alignment of the AJ-like and TJ-like domains was reversed by complementary expression of CPMs Par-3, atypical protein kinase C, Par-6, Crb3, Pals1 and Patj. We describe the cooperative roles of these CAMs and CPMs in the apico-basal alignment of TJs and AJs in epithelial cells. Show less