👤 Takeshi Nishikawa

Obesity, a risk factor for atherosclerosis development and progression, is marked by excessive reactive oxygen species (ROS) production. We previously demonstrated that high-glucose (HG) conditions induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the link between elevated mtROS levels in obesity and atherosclerosis progression remains unclear. This study aimed to investigate whether endothelial-specific mtROS suppression by overexpressing manganese superoxide dismutase (MnSOD) could attenuate atherosclerosis progression in high-fat diet (HFD)-induced obese apolipoprotein E-deficient (ApoE KO) mice. Atherosclerotic lesion formation did not differ significantly between normal chow-fed control ApoE KO mice and endothelial cell-specific MnSOD-overexpressing ApoE KO (eMnSOD-Tg/ApoE KO) mice. However, in HFD-fed groups, eMnSOD-Tg/ApoE KO mice exhibited reduced atherosclerotic lesion size, decreased relative ROS levels, and lower Our findings demonstrate that endothelial-specific MnSOD overexpression suppresses obesity-related atherosclerosis in ApoE KO mice. mtROS plays a pivotal role in obesity-associated atherosclerosis, and targeting endothelial mtROS may offer a therapeutic strategy for preventing vascular complications in obesity. Show less

Tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, was approved in Japan for the treatment of Waldenström's macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). We report the findings of post-marketing surveillance (PMS) of tirabrutinib that was started following its approval. We conducted an all-case PMS of patients who started tirabrutinib treatment between August 21, 2020, and January 17, 2021 for WM/LPL in Japan. Safety and effectiveness data were recorded for up to 52 weeks after the first dose of tirabrutinib. Among 152 patients who started tirabrutinib, 67.1% were male, 77.6% were ≥ 65 years old, and 61.8% started treatment with tirabrutinib at 480 mg/day (once-daily). Among these 152 patients, any-grade and grade ≥ 3 adverse drug reactions (ADRs) occurred in 58.6% and 29.6% of patients, respectively. The main ADRs were platelet count decreased (9.2%) and rash (9.2%). Grade 5 ADRs were reported in four patients (2.6%). The outcomes of most ADRs associated with the safety specifications (myelosuppression, infections, interstitial lung diseases, clinically significant skin disorders, hemorrhages, hepatic function disorders, and hypersensitivities) were resolved or improved. The effectiveness was assessed by the physicians using the VI Show less

An 88-year-old man was referred with peripheral edema, pleural effusion and nephrotic syndrome that had developed 3 months prior. Based on a kidney biopsy, the majority of glomeruli exhibited capillary wall thickening and the slight area of glomeruli exhibited spike formations and bubbly appearances. Fluorescent immunostaining showed global deposition of neural epidermal growth factor-like 1 (NELL-1), immunoglobulin (Ig) G1 and complement (C) 3c within the glomerular capillary wall. Electron microscopy showed the presence of unique subepithelial electron-dense deposits distributed in a ribbon-like manner along more than 75% of glomerular capillary walls. Fluorescent immunostaining showed no positivity for other recently identified antigens associated with membranous nephropathy, including M-type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), and exostosin 1 (EXT1). A comprehensive medical examination for malignant diseases yielded negative results, and there was no discernible change in κ/λ staining. Additionally, serum complement levels were within the normal range. The patient was therefore diagnosed with NELL-1-positive membranous nephropathy and has been refractory to the treatment with prednisolone, cyclosporine (CyA) and rituximab for 10 months. According to previous reports, segmental or incomplete IgG capillary loop staining have been observed in 93.4% of cases of NELL-1-positive membranous nephropathy. Diffuse and global ribbon-like deposits, as observed in this case, are exceedingly rare. Show less

Macroautophagy/autophagy plays a critical role in the pathogenesis of various human diseases including neurodegenerative disorders such as Parkinson disease (PD) and Huntington disease (HD). Chemical autophagy inducers are expected to serve as disease-modifying agents by eliminating cytotoxic/damaged proteins. Although many autophagy inducers have been identified, their precise molecular mechanisms are not fully understood because of the complicated crosstalk among signaling pathways. To address this issue, we performed several chemical genomic analyses enabling us to comprehend the dominancy among the autophagy-associated pathways followed by an aggresome-clearance assay. In a first step, more than 400 target-established small molecules were assessed for their ability to activate autophagic flux in neuronal PC12D cells, and we identified 39 compounds as autophagy inducers. We then profiled the autophagy inducers by testing their effect on the induction of autophagy by 200 well-established signal transduction modulators. Our principal component analysis (PCA) and clustering analysis using a dataset of "autophagy profiles" revealed that two Food and Drug Administration (FDA)-approved drugs, memantine and clemastine, activate endoplasmic reticulum (ER) stress responses, which could lead to autophagy induction. We also confirmed that SMK-17, a recently identified autophagy inducer, induced autophagy via the PRKC/PKC-TFEB pathway, as had been predicted from PCA. Finally, we showed that almost all of the autophagy inducers tested in this present work significantly enhanced the clearance of the protein aggregates observed in cellular models of PD and HD. These results, with the combined approach, suggested that autophagy-activating small molecules may improve proteinopathies by eliminating nonfunctional protein aggregates. Show less

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway. Show less