👤 Takashi Narita

Cardiac fibrosis drives dysfunction in dilated cardiomyopathy (DCM); yet, effective therapies are limited. This study identifies FGFR1 as a critical target in cardiac fibrosis using transcriptomic and histological analyses of 58 human DCM biopsies. FGFR1 expression correlated with fibrosis severity, and inhibition by AZD4547 reduced fibrosis and improved cardiac function in organoid and murine models. These findings validate FGFR1 inhibition as a promising therapeutic strategy for mitigating fibrosis and improving outcomes in heart failure associated with DCM. Show less

Background Idiopathic multicentric Castleman disease (iMCD) is a chronic inflammatory condition for which Janus kinase (JAK) inhibition has been hypothesized to be a potential treatment. However, filgotinib, a JAK1 preferential inhibitor, did not show apparent efficacy for iMCD in a clinical trial at eight weeks. This study aimed to compare the serum cytokine and chemokine profiles of patients treated with filgotinib with those of patients treated with tocilizumab to speculate why filgotinib was not effective at eight weeks. Methods This study included five patients treated with filgotinib who participated in a phase Ib single-arm clinical trial of filgotinib for iMCD and five tocilizumab-treated patients whose data were collected retrospectively. Serum levels of 41 cytokines/chemokines before and after treatment were measured. Results The tocilizumab group showed improvement in C-reactive protein, hemoglobin, and albumin levels after treatment while the filgotinib group showed no changes in these markers. The tocilizumab group showed significant changes in 12 cytokines/chemokines from baseline to after treatment, whereas the filgotinib group showed only a decrease in IL-18 and IL-27 levels. After treatment, significant differences were observed between the two groups for 10 cytokines/chemokines. Five cytokines (FGF-2, IL-4, IL-6, TNF-β, and VEGF-A) showed significant changes after tocilizumab treatment and differences between the tocilizumab and filgotinib groups after treatment. Conclusion This study identified FGF-2, IL-4, IL-6, TNF-β, and VEGF-A as potential factors that could explain the lack of apparent efficacy of filgotinib in iMCD treatment at eight weeks. These findings may contribute to future drug development for iMCD. Show less

Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115 Show less

Liver X receptors (LXR) α and β are a family of nuclear receptors that regulate lipogenesis by controlling the expression of the genes involved in the synthesis of fatty acids. MID1IP1, which encodes MIG12, is a target gene of LXR. MIG12 induces fatty acid synthesis by stimulating the polymerization-mediated activation of acetyl-CoA carboxylase (ACC). Here, we show that LXR's activation stimulates ACC polymerization in HepG2 cells by increasing the expression of MIG12. A knockdown of MID1IP1 abrogated the stimulation completely. The mutations of MIG12's leucine-zipper domain reduced the interaction between MIG12 and ACC, thus decreasing the MIG12's capacity to stimulate ACC polymerization. These results indicate that LXR's activation stimulates lipogenesis not only through the induction of the genes encoding lipogenic enzymes but also through MIG12's stimulation of ACC polymerization. Show less

Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic β-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue. Gipr We observed that GIP receptor-knockout (Gipr Although maintenance of CR is difficult, food intake and muscle endurance of Gipr Show less

In addition to overeating, starvation also reduces fecundity in mammals. However, little is known about the molecular mechanisms linking food intake to fertility, especially in males. Gastric inhibitory polypeptide (GIP), which is released from intestinal K-cells after meal ingestion, stimulates insulin secretion from pancreatic β-cells through the action of incretin and has several extrapancreatic effects. Here, we identified GIP receptor (Gipr) expression in mouse spermatids. Microarray analysis revealed that pregnancy-specific glycoprotein 17 (Psg17), a potential CD9-binding partner, was significantly decreased in GIP receptor-knockout (Gipr-/-) testes. Glycosylphosphatidylinositol-anchored PSG17 was expressed on the surface of acrosome-reacted sperm, and Gipr-/- sperm led to a lower fertilization rate in vitro, compared with that of Gipr+/+ sperm, both in the absence and presence of the zona pellucida. Plasma GIP concentrations and Psg17 messenger RNA (mRNA) were immediately increased in the testis after a single meal, whereas ingestion of a chronic high-fat diet markedly decreased Gipr and Psg17 mRNA. These results suggest that reduced GIP signaling, by decreased GIP levels or the downregulation of Gipr, is associated with the reduction of fecundity due to starvation or overeating. Thus, proper regulation of GIP signaling in the testis could be a potential unique therapeutic target for male infertility in obese and diabetic individuals. Show less

The 17beta-hydroxysteroid dehydrogenases (HSDs) are enzymes that catalyze the reduction of 17-ketosteroids or the oxidation of 17beta-hydroxysteroids. 17beta-HSD type 12, the most recently cloned member of this gene family, was classified into the 17beta-HSD family based on sequence homology, rather than steroid catalyzing activity. Meanwhile, it has been reported that 17beta-HSD type 12 may be involved in fatty acid synthesis. To better understand the role of 17beta-HSD type 12 in lipid metabolism, we determined the detailed systemic distribution and tissue localizations of 17beta-HSD type 12, which, due partly to the lack of antibodies, had not yet been studied. We carried out these investigations by quantitative reverse transcription (RT)-PCR, Northern blot analysis, and immunohistochemistry, using an antibody against 17beta-HSD type 12 that we have generated. 17beta-HSD type 12 is highly expressed in organs related to lipid metabolism such as liver, kidney, heart and skeletal muscle. 17beta-HSD type 12 is also detected in endocrine-related organs such as pancreas, pituitary gland, adrenal gland, testis and placenta, and in the gastrointestinal tract, which point to the possible involvement of 17beta-HSD type 12 in the regulation of lipid biosynthesis and steroid metabolism. These results support previous reports and solidify the possibility that 17beta-HSD type 12 may play critical roles in the physiological processes, such as fatty acid synthesis, in addition to the steroid metabolism. Show less