👤 Takeshi Uehara

Adiponectin is an anti-diabetic and anti-atherogenic protein secreted primarily from adipose tissue. Adiponectin and modified LDL (mLDL) form a complex to modulate their biological activity. To elucidate the significance of the complex formation, we analyzed its effects on vascular tissue and developed and verified novel quantifying methods for adiponectin. To study the significance of the mLDL-adiponectin complex (MAC) formation, we used the wire-myography method on rat mesenteric artery. We developed a method to measure MAC by using LOX-1 as the capture protein and anti-adiponectin antibody for detection. We compared serum MAC levels between hemodialysis patients and control subjects. Administering mLDL alone to rat mesenteric artery impaired endothelium-dependent vasorelaxation, whereas simultaneously administering adiponectin with mLDL protected rat mesenteric artery from the mLDL-induced impairment of vasorelaxation. This finding indicates MAC formation prevents endothelium from mLDL-induced dysfunction in tissue. Using our novel ELISA for MAC, we found that MAC was increasingly detectable depending on the doses of mLDL and adiponectin in vitro. In serum, hemodialysis patients showed a significantly higher ratio of MAC-high patients (higher than the median level of MAC) than did healthy controls. Furthermore, the MAC-high hemodialysis group had lower mLDL activity measured as LOX-1 ligand containing apoB. Using our ELISA, we detected MAC in human serum that protected blood vessels from the deleterious effects of oxidized LDL. Show less

We demonstrated that low-intensity pulsed ultrasound (LIPUS) therapy tended to ameliorate cognitive declines in patients with early Alzheimer's disease (AD) in the pilot trial. Thus, we have started the pivotal trial in a randomized, double-blind, placebo-controlled manner (LIPUS-AD). We here report the clinical characteristics of AD patients enrolled in the trial. The major inclusion criteria included age 50-90 years of both sex, Clinical Dementia Rating (CDR) global score of 0.5∼1.0 and Japanese version of the Mini-Mental State Examination (MMSE-J) score greater than 20 at screening, positive brain Aβ-PET, and no symptomatic brain hemorrhage, infarction, or edema on brain MRI. A total of 231 subjects were finally enrolled. As compared with the pilot trial, they were characterized by older age and higher prevalence of dyslipidemia. They had lower scores of ADAS-J-cog and Modified Hachinski Ischemic Scale (MHIS), while other cognitive scores were comparable with the pilot trial. Use of cholinesterase inhibitors was less as compared with the pilot trial. Clinical characteristics of subjects in the LIPUS-AD trial largely mimic those in the pilot trial, addressing efficacy and safety of the LIPUS therapy in early AD.Clinical Trial Gov. No.: NCT05983575, jRCT No.: jRCT2032230125. Show less

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH) Show less

The global distribution of lipoprotein(a) [Lp(a)] levels varies due to racial and ethnic differences. However, the clinical relevance of Lp(a) levels in Japanese patients has not been fully explored. We investigated the association of Lp(a) levels, the Suita score, and the presence of high-risk plaque (HRP) as well as that of ≥ 50% stenosis, quantitative plaque volume, and the value of coronary artery calcium score in coronary computed tomographic angiography (CCTA), among 272 Japanese patients (mean age: 65 years) in whom serum Lp(a) levels were measured due to suspected coronary artery disease. HRP was defined as positive remodeling and/or low attenuation. Plaque volume was quantified as the percent plaque volume. HRP was identified in 33 (12.1%) patients. The prevalence of HRP, ≥ 50% stenosis, and percent plaque volume progressively increased with higher Lp (a) levels and Suita scores. In multivariate analyses, Lp(a) and the Suita score independently predicted HRP when assessed as continuous (p = 0.02, p＜0.001, respectively) or categorical variables (p = 0.005, p = 0.007, respectively). Patients in the highest tertile of Lp(a) and classified as high- or intermediate-risk by the Suita score had the highest HRP risk, whereas those in the lower 2 tertiles and low-risk group had the lowest. Incorporating Lp(a) into the Suita score improved the prediction of HRP beyond the Suita score alone (p = 0.005). The combinatorial value of assessing Lp(a) levels and Suita score may provide useful insight regarding Japanese patients undergoing CCTA for the prediction of HRP. Show less

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors with high mortality. Anoikis resistance is an important mechanism of tumor cell proliferation and migration. Our research is devoted to exploring the role of anoikis in the diagnosis, classification, and prognosis of LUAD. We downloaded the expression profile, mutation, and clinical data of LUAD from The Cancer Genome Atlas (TCGA) database. The "ConsensusClusterPlus" package was then used for the cluster analysis, and least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were used to establish the prognostic model. We verified the reliability of the model using a Gene Expression Omnibus (GEO) data set. A gene set variation analysis (GSVA) was conducted to investigate the functional enrichment differences in the different clusters and risk groups. The CIBERSORT algorithm and a single-sample gene set enrichment analysis (ssGSEA) were used to analyze immune cell infiltration. The tumor mutation burden (TMB) and Tumor Immune Dysfunction and Exclusion (TIDE) scores were used to evaluate the patients' sensitivity to immunotherapy. Immunohistochemical staining of tissue microarrays was used to verify the correlation between ANGPTL4 expression and the clinicopathological characteristics and prognosis of LUAD patients. First, we screened 135 differentially expressed anoikis-related genes (ARGs) and 23 prognosis-related ARGs from TCGA-LUAD data set. Next, 494 LUAD samples were allocated to cluster A and cluster B based on the 23 prognosis-related ARGs. The Kaplan-Meier (K-M) analysis showed the overall survival (OS) of cluster B was better than that of cluster A. The clinicopathological characteristics and functional enrichment analyses revealed significant differences between clusters A and B. The tumor microenvironment (TME) analysis showed that cluster B had more immune cell infiltration and a higher TME score than cluster A. Subsequently, a LASSO Cox regression model of LUAD was constructed with ten ARGs. The K-M analysis showed that the low-risk patients had longer OS than the high-risk patients. The receiver operating characteristic curve, nomogram, and GEO data set verification results showed that the model had high accuracy and reliability. The level of immune cell infiltration and TME score were higher in the low-risk group than the high-risk group. The high-risk group had stronger sensitivity to immune checkpoint block therapy and weaker sensitivity to chemotherapy drugs than the low-risk group. ANGPTL4 expression was correlated with stage, tumor differentiation, tumor size, lymph node metastasis, and OS. We discovered novel molecular subtypes and constructed a novel prognostic model of LUAD. Our findings provide important insights into subtype classification and the accurate survival prediction of LUAD. We also identified ANGPTL4 as a prognostic indicator of LUAD. 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

Passive membrane permeability and an active transport process are key determinants for penetrating the blood-brain barrier. P-glycoprotein (P-gp), a well-known transporter, serves as the primary gatekeeper, having broad substrate specificity. A strategy to increase passive permeability and impair P-gp recognition is intramolecular hydrogen bonding (IMHB). Show less

Aducanumab, co-developed by Eisai (Japan) and Biogen (U.S.), has received Food and Drug Administration approval for treating Alzheimer's disease (AD). In addition, its successor antibody, lecanemab, has been approved. These antibodies target the aggregated form of the small peptide, amyloid-β (Aβ), which accumulates in the patient brain. The "amyloid hypothesis" based therapy that places the aggregation and toxicity of Aβ at the center of the etiology is about to be realized. However, the effects of immunotherapy are still limited, suggesting the need to reconsider this hypothesis. Aβ is produced from a type-I transmembrane protein, Aβ precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called βCTF), is a direct precursor of Aβ and accumulates in the AD patient's brain to demonstrate toxicity independent of Aβ. Conventional drug discovery strategies have focused on Aβ toxicity on the "outside" of the neuron, but C99 accumulation might explain the toxicity on the "inside" of the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and Aβ is a promising target for multifunctional AD drugs. This review aimed to outline the nature, metabolism, and impact of C99 on AD pathogenesis and discuss whether it could be a therapeutic target complementing the amyloid hypothesis. 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

Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, reportedly reduces cardiovascular events in diabetic patients. ATP cassette binding transporters (ABC) A1 and G1 are pivotal molecules for cholesterol efflux (ChE) from macrophages and high density-lipoprotein biogenesis, and the A1 transporter is regulated by a PPARγ-liver receptor X (LXR) pathway. Also, pioglitazone induces ABCG1 expression, though the exact mechanism remains unclear. We therefore investigated the effects of pioglitazone on ABCA1/G1 expression in vitro and ex vivo. The effects of pioglitazone on ChE and ABCA1/G1 expressions in macrophages were assessed. Then, mRNA was quantified in macrophages when PPARγ/LXR inhibition by siRNA or overexpression of oxysterol sulfotransferase was performed. ABCA1/G1 promoter activity with mutated LXR-responsive elements was also measured. As an ex vivo study, 15 type 2 diabetic patients were administered pioglitazone or placebo, and ChE assays and protein expressions were determined using macrophages cultured with the corresponding sera. Pioglitazone increased LXRα/ABCA1/G1 expressions, which enhanced ChE from macrophages. Inhibition of PPARγ/LXR pathways revealed that LXR was primarily involved in pioglitazone's transactivation of ABCA1 but only partially involved for ABCG1. Promoter assays showed that ABCG1 was regulated more by the promoter in intron 4 than that upstream of exon 1 but both promoters were responsive to LXR activation. Sera obtained after pioglitazone treatment promoted ChE and ABCA1/G1 expressions in macrophages. Pioglitazone enhanced ChE from macrophages by increasing ABCA1/G1 in LXR-dependent and -independent manners. Our comparable in vitro and ex vivo results shed new light on pioglitazone's novel anti-atherogenic property. Show less

The apolipoprotein A5 gene (ApoA5) plays an important role in modulating triglyceride metabolism. Polymorphisms of ApoA5, including -1131T>C and c.553G>T (G185C), have been reported to correlate with hypertriglyceridemia (HTG). In the present study the relationships of 5 single nucleotide polymorphisms, including the -1131T>C, c.56C>G, IVS3+476G>A, c.553G>T, and c.1259T>C polymorphisms of ApoA5, with HTG were investigated. The study group comprised 95 Japanese patients with HTG and 119 unrelated normolipidemic subjects. Frequencies of the C allele of -1131T>C (0.511) and the T allele of c.553G>T (0.205) in the hypertriglyceridemic patients were significantly higher than in the normolipidemic subjects (0.315 and 0.105, respectively). The c.56C>G (S19W) polymorphism was not observed, and the other 4 polymorphic sites were in strong linkage disequilibrium. Five of the 8 detected haplotypes with the C allele of -1131T>C correlated with HTG. Promoter activities of ApoA5, including that with the -1131T>C polymorphism, were estimated using a luciferase assay. Analysis of ApoA5 promoters showed that the -1131T>C polymorphism alone had no effect. Comparison of expression of mutant G185C and wild-type ApoA5-green fluorescent protein (GFP) in HepG2 cells showed that ApoA5-GFP was abundant in punctate endosome-like structures, and ApoA5 (G185C)-GFP expression resembled that of the wild type. The -1131T>C and c.553G>T (G185C) polymorphisms correlated with HTG in this Japanese population, but neither polymorphism directly affected ApoA5 expression. Show less

DUSP6/MKP-3, a specific inhibitor of MAPK1/ERK2, frequently loses its expression in primary pancreatic cancer tissues. This evidence suggests that constitutive activation of MAPK1 synergistically induced by frequent mutation of KRAS2 and the loss of function of DUSP6 plays key roles in pancreatic carcinogenesis and progression. By profiling of gene expressions associated with downregulation of MAPK1 induced by exogenous overexpression of DUSP6 in pancreatic cancer cells, we found that AURKA/STK15, the gene encoding Aurora-A kinase, which plays key roles in cellular mitosis, was among the downregulated genes along with its related genes, which included AURKB, TPX2 and CENPA. An association of expression and promoter activity of AURKA with MAPK activity was verified. Knockdown of ETS2 resulted in a reduction of AURKA expression. These results indicate that AURKA is a direct target of the MAPK pathway and that its overexpression in pancreatic cancer is induced by hyperactivation of the pathway, at least via ETS2. Show less