👤 Ryoko Oyama

Studies on light-elicited endothelial period circadian regulator 2 (PER2) mediated cardioprotection revealed a critical role of PER2/hypoxia inducible factor 1 alpha (HIF1A) regulated endothelial factor ANGPTL4 for endothelial barrier protection during myocardial ischemia and reperfusion injury (IRI). Based on these observations, we deepened our studies on light-elicited cardioprotective mechanisms. All animal and human studies had Institutional Animal Care and Use Committee (IACUC) and Colorado Multiple Institutional Review Board (COMIRB) approval. To study myocardial IRI, an in-situ mouse model for myocardial IRI was used. To study light-elicited mechanisms during myocardial IRI, endothelial-specific The PER2 enhancer NOB or the HIF1A activator DMOG protected from myocardial IRI, which was abolished in endothelial-specific Our study demonstrates that only the PER2/HIF1A downstream target ANGPTL4 can overcome an endothelial Show less

Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disorder involving bile acid biosynthesis. Reduced mitochondrial cytochrome P450 enzyme activity leads to abnormal lipid accumulation in various tissues, especially tendons, lenses, and the central and peripheral nervous systems. This condition manifests with systemic symptoms such as neurological disorders, atherosclerosis, tendon xanthomas, and cataracts. Cerebrotendinous xanthomatosis typically presents in individuals with homozygous or compound heterozygous mutations in the CYP27A1 gene because of its autosomal recessive inheritance pattern. However, the phenotypic expression in heterozygous carriers remains uncertain. We report a 53-year-old Japanese man who was clinically diagnosed with familial hypercholesterolemia. He presented with marked Achilles tendon xanthomas and refractory hyper-low-density-lipoprotein cholesterolemia. Initiation of intensified lipid-lowering therapy, including inclisiran, resulted in improvement of hyper-low-density-lipoprotein cholesterolemia. Genetic testing revealed heterozygous mutations in CYP27A1 (p.Arg405Gln) and apolipoprotein B (APOB) (p.Pro955Ser). He had no neurological symptoms, cataracts, or other features suggestive of cerebrotendinous xanthomatosis without Achilles tendon xanthomas. This case highlights a rare presentation of a potential CYP27A1 heterozygous mutation-related phenotype. The APOB (p.Pro955Ser) variant is associated with reduced low-density-lipoprotein receptor activity, contributing to hyper-low-density-lipoprotein cholesterolemia and Achilles tendon xanthomas. However, this patient's Achilles tendon xanthoma was thicker than those reported in previous cases with APOB (p.Pro955Ser) gene mutations, suggesting a potential contribution from the CYP27A1 mutation. Although the patient did not exhibit elevated serum cholestanol levels or other cerebrotendinous xanthomatosis features, the marked Achilles tendon thickening raises the possibility that the combination of a heterozygous CYP27A1 gene mutation and an APOB gene mutation contributed to the condition. Show less

Long-persistent luminescent (LPL) materials store photon energy as charges and emit light over extended periods via charge recombination. LPL decay typically follows a power law rather than an exponential decay, enabling confirmation of charge accumulation from emission decay characteristics. While charge generation in organic materials has been widely studied at donor-acceptor (D/A) interfaces, it remains underexplored in single-component luminescent materials. Here, we investigate charge generation in organic solids by dispersing a luminescent molecule in various hosts and performing slow transient emission analyses. This approach enables the evaluation of ionization through accumulated triplet excited states and the detection of weak charge accumulation, which are difficult to capture using conventional transient techniques. Our results show that ionization in single-component materials proceeds through resonance-enhanced multiphoton ionization, although it is less efficient than at D/A interfaces. This approach provides insight into long-term photophysical and photochemical processes such as photodegradation. Show less

Organic materials exhibiting long-lasting emission in the near infrared are expected to have applications in bio-imaging and other areas. Although room temperature phosphorescence and thermally activated delayed fluorescence display long-lived emission of approximately one minute, organic long-persistent luminescence (OLPL) systems with a similar emission mechanism to inorganic persistent emitters can emit for several hours at room temperature. In particular OLPL with a hole-diffusion mechanism can function even in the presence of oxygen. However, ionic materials lack long-term stability in neutral organic host owing to aggregation and phase separation. In this study, we synthesized polymers with stable near-infrared persistent luminescence at room temperature via the copolymerization of electron donors and acceptors. The copolymers exhibit long-persistent luminescence (LPL) at temperatures below the glass transition temperature and can be excited by approximately the entire range of visible light. LPL properties and spectra can be controlled by the dopant. Show less

Angiopoietin-like 4 (ANGPTL4) is critical for regulating plasma lipids, and thus an attractive therapeutic target for cardiovascular diseases. Unfortunately, targeting ANGPTL4 results in a proinflammatory and ultimately lethal phenotype in animals. The serendipitous discovery of cardiac ANGPTL4 as a circadian protein reveals novel mechanistic insight and a solution for this therapeutic dilemma. Show less

Physical inactivity has emerged as an important cardiometabolic risk factor; however, the beneficial impacts of physical exercise according physical fitness status are still unclear. To analyze the lipoproteins and immune-endocrine response to acute aerobic exercise sessions performed at different intensities according physical fitness status and evaluated the gene expression in monocyte cells. Twelve individuals, divided into Low and High VO Show less

Contradictory results are reported for the role of angiopoietin-like 4 (ANGPTL-4) in the development of cancer-cachexia and inflammation, given its importance in angiogenesis and inflammatory signaling. Our aim was to analyze the levels of ANGPTL-4 in colorectal cancer patients with a stable weight and those with cachexia in order to establish a relationship between ANGPTL-4 and the inflammatory process. Plasma and tumor levels of ANGPTL-4 were higher in CC in comparison to other groups. A positive association was verified between plasmatic ANGPTL-4 and NFκB levels in tumor from CC. In WSC, we identified an association between the plasmatic ANGPTL-4, IL-15, and IL-10 in tumor and IL-15 in MES. Increased levels of NFκB and TNF-R1 in MES were detected in CC in comparison to WSC. Specifically in CC-group, a positive correlation was found between ANGPTL-4 levels and those of IL-1β, TNF-α, and NFκB in tumor, along with an association between ANGPTL-4 levels with IL-1β and MCP-1 levels in tumor; and ANGPTL-4 and IL-1β levels in MES. We studied 102 patients, who were divided into three groups: control patients (C, n=37), cancer patients with a stable weight (WSC, n=23), and cancer-cachexia patients (CC, n=42). Samples of plasma, tumor, mesenteric (MES) and subcutaneous adipose tissue were removed for the determination of ANGPTL-4 levels and other proinflammatory factors. ANGPTL-4 levels were higher in plasma and tumor of CC-group, and positively associated with pro-inflammatory and pro-tumorigenic factors. Our results suggest an opposite effect of ANGPTL-4 depending on the concentration and presence of cachexia. Show less

Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury. We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1+/-), SMC-specific Notch1 heterozygous deficient (smN1+/-), and general Notch3 homozygous deficient (N3-/-) mice. Compared with wild-type or control mice, N1+/- and smN1+/- mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3-/- mice. Indeed, SMCs derived from explanted aortas of either N1(+/-)- or smN1+/- mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3-/- mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1(+/-)- or smN1+/- mice. In SMCs derived from CHF1/Hey2-/- mice, activation of Notch signaling did not lead to increased SMC proliferation or migration. These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases. Show less

Bone marrow- (BM-) derived cells can differentiate into smooth muscle-like cells (SMLC), resulting in vascular pathogenesis. However, the molecular mechanism of the differentiation remains unknown. We have recently reported that Notch signaling promotes while a Notch target HERP1 inhibit the differentiation of mesenchymal cells to SMC. During the differentiation of BM-derived mononuclear cells into smooth muscle alpha-actin (SMA)-positive cells, expression of Jagged1 and SMC-specific Notch3 was increased. Blocking Notch with gamma-secretase inhibitor prevented the induction of SMA. Wire-mediated vascular injury was produced in femoral arteries in mice transplanted with green fluorescent protein (GFP)-positive cells. Many double-positive cells for GFP/Jagged1 or GFP/Notch3 were detected in the thickened neointima. In contrast, only a few SMA-positive cells were positive for GFP in neointima where HERP1, a suppressor for Notch, were abundantly expressed. In conclusion, Notch-HERP1 pathway plays an important role in differentiation of BM-derived mononuclear cells into SMLC. Show less