Biomedical subjects

Nobuyuki Takahashi

Publications and source records attributed to Nobuyuki Takahashi.

At least 19 recordsLinked to original sources

PubMed2026

A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy.

Small-cell lung cancer (SCLC) is an aggressive malignancy with substantial tumor heterogeneity and limited clinically actionable biomarkers beyond established features such as liver metastases. We profile tumor-intrinsic chromatin accessibility in a patient-derived xenograft biobank and identify three recurrent chromatin programs: neuroendocrine, marked by ASCL1/NEUROD1 activity; immunogenic, marked by IRF-associated activity; and stem-like, marked by TEAD/OCT activity. These programs are reproduced at the cohort level across bulk and single-cell transcriptomic datasets comprising more than 800 tumors, including 300 extensive-stage samples. In patients treated with chemoimmunotherapy, the stem-like program is associated with inferior survival, including a median overall survival of 7.41 months versus 15.9 and 12.6 months for immunogenic and neuroendocrine groups, respectively. This association remains significant after adjustment for liver metastases, brain metastases, and elevated lactate dehydrogenase. These findings support a high-risk stem-like SCLC chromatin program for prospective biomarker refinement and therapeutic investigation.

ATAC-seq↗

PubMed2025

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol. 26, 2651-2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus 9, 258-275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun. 2, 503-517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

Lamin Type A↗

PubMed2025

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNA's role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging.

Biological Sciences↗

PubMed2004

Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.

Type I human diabetics and streptozotocin-induced diabetic mice with higher genetically determined levels of angiotensin-converting enzyme have an increased risk of developing nephropathy. However, previous experiments in mice and computer simulations indicate that modest increases in angiotensin-converting enzyme have minimal effects on blood pressure and angiotensin II levels, although bradykinin decreases significantly, inferring that bradykinin is critical for protecting the kidney in diabetics. Here, we confirm this inference by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor develop overt albuminuria, excreting the equivalent of >550 mg/day albumin in humans, which contrasts with the microalbuminuria (equivalent to <150 mg/day) seen in their simply diabetic littermates. The overt albuminuria is accompanied by a marked increase in glomerular mesangial sclerosis. The importance of bradykinin demonstrated here bears strongly on how current drugs reduce diabetic nephropathy and suggests that B2 receptor-specific agonists merit consideration in this context.

Animals↗

PubMed2004

Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPARgamma ligand-like action as a novel mechanism.

Capsaicin, a major ingredient of hot pepper, is considered to exhibit anti-inflammatory properties. Our previous study demonstrated that capsaicin inhibited the production of pro-inflammatory mediators through NF-kappaB inactivation in LPS-stimulated macrophages. In order to further clarify the mechanism underlying the anti-inflammatory action of capsaicin, we investigated whether capsaicin alters PPARgamma activity, which regulates the production of the pro-inflammatory cytokine TNFalpha. Capsaicin significantly inhibited the production of TNFalpha by macrophages in a dose-dependent manner. Simultaneous exposure of the cells to capsaicin and PPARgamma agonist troglitazone or RXR agonist LG100268 resulted in stronger inhibition of TNFalpha production compared to the cells treated with either capsaicin, troglitazone, or LG100268 alone. Luciferase reporter assay revealed that capsaicin induced GAL4/PPARgamma chimera and full length PPARgamma (PPRE) transactivations in a dose-dependent manner. Furthermore, a specific PPARgamma antagonist T0070907 abrogated the inhibitory action of capsaicin on LPS-induced TNFalpha production by RAW 264.7 cells, indicating that capsaicin acts like a ligand for PPARgamma. Our data demonstrate for the first time that the anti-inflammatory action of capsaicin may be mediated by PPARgamma activation in LPS-stimulated RAW 264.7 cells.

Animals↗

PubMed2004

High-resolution MR imaging of the elbow using a microscopy surface coil and a clinical 1.5 T MR machine: preliminary results.

OBJECTIVE: To obtain high-resolution MR images of the elbow using a microscopy surface coil with a 1.5 T clinical machine and to evaluate the feasibility of its use for elbow injuries. DESIGN AND PATIENTS: Five asymptomatic normal volunteers and 13 patients with elbow pain were prospectively studied with MR imaging using a microscopy surface coil 47 mm in diameter. High-resolution MR images using a microscopy coil were obtained with fast spin echo (FSE) proton density-weighted sequence, gradient recalled echo (GRE) T2*-weighted sequence, and short tau inversion recovery (STIR) sequence, with a 1-2 mm slice thickness, a 50-70 mm field of view, an imaging matrix of 140-224 x 512 using zero fill interpolation, and 2-6 excitations. RESULTS: High-resolution MR images of normal volunteers using a microscopy coil clearly showed each structure of the medial and lateral collateral ligaments on GRE T2*-weighted images and FSE proton-density weighted images. Partial medial collateral ligament injury, a small avulsion of the medial epicondyle, and osteochondritis dissecans were well demonstrated on high-resolution MR images. CONCLUSION: High-resolution MR imaging of the elbow using a microscopy surface coil with a 1.5 T clinical machine is a promising method for accurately characterizing the normal anatomy of the elbow and depicting its lesions in detail.

Adolescent↗

PubMed2004

Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes.

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine secretion or the adipocyte-specific gene expression is one of the most important targets for the prevention of obesity and amelioration of insulin sensitivity. In this study, we demonstrated that anthocyanins (cyanidin or cyanidin 3-glucoside) have the potency of a unique pharmacological function in isolated rat adipocytes. Treated adipocytes with anthocyanins enhanced adipocytokine (adiponectin and leptin) secretion and up-regulated the adipocyte specific gene expression without activation of PPARgamma in isolated rat adipocytes. The gene expression of adiponectin was also up-regulated in white adipose tissue in mice fed an anthocyanin supplemented diet. As one of the possible mechanisms, AMP-activated protein kinase activation would be associated with these changes, nevertheless, the AMP:ATP ratio was significantly decreased by administration of the anthocyanins. These data suggest that anthocyanins have a potency of unique therapeutic advantage and also have important implications for preventing obesity and diabetes.

AMP-Activated Protein Kinases↗

PubMed2004

Magnetic resonance imaging evaluation of cooling on blood flow and oedema in skeletal muscles after exercise.

This study assessed the effects of cooling on blood flow and intramuscular water content in human skeletal muscles after exercise using magnetic resonance imaging. In six male subjects, their legs were randomly assigned to be control or to be cooled. All subjects performed ankle dorsiflexion exercise inside an imaging magnet and after exercise, an ice bag was placed on the ankle dorsiflexors of the cooled leg. Flow-sensitive images, which reflect both perfusion and intramuscular water, were obtained before and up to 270 s post-exercise at 30-s intervals. The flow-sensitive alternating inversion recovery (FAIR) images, which extract only the perfusion change, were also obtained. Signal intensity (SI) in the ankle dorsiflexors was estimated before and after exercise in both flow-sensitive and FAIR images. On the flow-sensitive images, the control leg increased SI 30-270 s after exercise (P<0.05), but the cooled leg showed no significant change. On the FAIR images, the control leg increased SI 30-270 s post-exercise (P<0.05), while the cooled leg increased SI 30-150 s and 210 s after exercise (P<0.05). The findings suggest that cooling attenuates the perfusion elevation and prevents the oedema formation in skeletal muscle immediately after exercise.

Adult↗

PubMed2004

Expression of novel isoforms of the CIC-1 chloride channel in astrocytic glial cells in vitro.

Chloride channels play an important role in glial astrocyte function. However, in astrocytes, no chloride channels besides the gamma-aminobutyric acid (GABA)A receptor, glycine receptor, and ClC-2 chloride channels have been molecularly identified. In this study, we examined the expression of the ClC-1 chloride channel in rat astrocytic glioma C6 cells and rat primary astrocytes. Five isoforms of ClC-1, but not skeletal muscle ClC-1 (SM ClC-1), were found to be expressed in C6 cells. Comparison with rat SM ClC-1 showed that common features shared by these isoforms are a short 3' end with a deletion of the nucleotides from 3115 to 3197 and a substitution of T by C at nucleotides 480 and 1733. Three of the five isoforms, M1, M2, and M3, were produced by partial deletion of ClC-1 exon 7, partial insertion of ClC-1 exon 7a, and a TAG insertion at nucleotide 858, respectively. One of the two remaining isoforms, M4, was produced by partial deletion of ClC-1 exon 8 at nucleotide 937; the other, M5, was the same as SM ClC-1 except for the short 3' end and substitutions at the two positions. Only the M5 isoform could be expressed as a functional channel in Xenopus oocytes. This glial isoform exhibited less dependence on voltage and extracellular Cl- than rat SM ClC-1. However, the anion selectivity sequence and the anthracene-9-carboxylic acid (9-AC) sensitivity of this channel were the same as for SM ClC-1. Since whole-cell recordings failed to detect ClC-1-like Cl- currents in C6 cells, it appears that the ClC-1 isoform is functioning in intracellular organelles. In rat primary astrocytes, we found that the M2 isoform as well as two additional distinct isoforms were expressed. The present study showed that astrocytic glial cells express multiple isoforms of the ClC-1 chloride channel, which has been thought to be expressed almost exclusively in the skeletal muscle.

Animals↗

PubMed2004

Malaria dispersal among islands: human mediated Plasmodium falciparum gene flow in Vanuatu, Melanesia.

A comparison of human and Plasmodium falciparum gene flow patterns in the model island system of Vanuatu, the limit of malaria in the Pacific reveals that human movement is essential for long, but not short distance P. falciparum gene flow. This suggests that long distance movement of humans may accelerate the evolution and spread of drug resistance and therefore exacerbate the global malaria problem.

Animals↗

PubMed2004

Probucol and ticlopidine: effect on platelet and monocyte activation markers in hyperlipidemic patients with and without type 2 diabetes.

We investigated the effects of probucol and ticlopidine on circulating levels of platelet activation markers, microparticles, soluble selectins, and malondialdehyde-low density lipoprotein (MDA-LDL) in hyperlipidemic patients with or without type 2 diabetes. There were significant differences in the levels of CD62P, PAC-1, annexin V, PDMP, MDMP, sP-selectin, sE-selectin and MDA-LDL between the hyperlipidemic patients and the controls. In particular, these markers were significantly increased in hyperlipidemic patients who had type 2 diabetes. In the hyperlipidemic patients with diabetes, MDA-LDL was decreased by both monotherapy with probucol and combination therapy (probucol and ticlopidine). In these patients, CD62P, PAC-1, annexin V, MDMP, PDMP, sP-selectin, and sE-selectin were also significantly decreased after treatment. The decreases of CD62P, PAC-1, annexin V, PDMP and sP-selectin were greater combination therapy than with monotherapy. These findings suggest that administration of probucol and ticlopidine to hyperlipidemic patients with type 2 diabetes may help to prevent the development of cardiovascular complications caused by modified LDL, selectins, or activated platelets and monocytes.

Aged↗

PubMed2004

Three-dimensional fast field echo MR myelography using water excitation.

The purpose of this study is to determine if 3D FFE MRM using WE provides better image quality in comparison with that using SPIR. Twenty subjects were referred for the MRM images using SPIR, and WE with different TR. SNR and CNR were measured in the ganglions and adjacent tissues, in addition, the uniformity of the fat tissues was scored on a three-point scale by two radiologists with consensus. The WE sequence showed the higher SNR and CNR values than that using SPIR, in addition, the WE technique was helpful to achieve the shorter acquisition time of MRM.

Adolescent↗

PubMed2004

Dual double arterial phase dynamic MR imaging with sensitivity encoding (SENSE): which is better for diagnosing hypervascular hepatocellular carcinomas, in-phase or opposed-phase imaging?

The purpose of this study was to investigate the efficacy of sensitivity encoding (SENSE) dynamic magnetic resonance imaging (MRI) with the dual (in-phase and opposed-phase) double arterial phase to detect hypervascular hepatocellular carcinomas (HCCs). MR images of the liver from 44 consecutive patients were obtained. Dynamic MRI with SENSE was performed six times (precontrast, early arterial, late arterial, 1 min, 3 min and 5 min after contrast injection) at 11 s per scan using the gradient recalled echo sequence (TR/TE/flip angle = 168/2.3 and 4.6/70). In-phase and opposed-phase images were obtained simultaneously each scan. For the quantitative analysis, the signal-to-noise ratio (S/N) of HCC and tumor-to-liver contrast-to-noise ratio (C/N) were analyzed for 55 HCCs. The mean S/N of HCCs on in-phase images showed significantly higher values than that on opposed-phase images regarding all phases (P < 0.001). In arterial phases, the mean tumor-to-liver C/N for in-phase images was significantly higher than that for opposed-phase images (P < 0.05). In portal and delayed-phase images, the mean tumor-to-liver C/N in opposed-phase images showed a negative value. In six HCCs with fatty metamorphosis, the mean tumor-to-liver C/N on arterial phase images approached zero in opposed-phase, while it showed a positive value in-phase. In dual double arterial phase dynamic MRI of the liver, in-phase images were superior to opposed-phase images for detecting early enhancement of hypervascular HCCs, while the latter were superior for detecting washout of contrast media from HCCs in the portal and delayed phase. The combination of both images overcomes the difficulty of diagnosing hypervascular HCCs with fatty metamorphosis.

Aged↗

PubMed2004

Human genetics, animal models and computer simulations for studying hypertension.

Essential hypertension is probably caused by combinations of small quantitative changes in the expression of many genes together with environmental factors. In this article, strategies for studying hypertension using animal models are summarized with emphasis on the combined use of mouse models and computer simulations. We have chosen the rennin-angiotensin system as our main example. Future directions of hypertension research using gene targeting are also discussed.

Animals↗

PubMed2004

Altering the expression in mice of genes by modifying their 3' regions.

Polymorphic differences altering expression of genes without changing their products probably underlie human quantitative traits affecting risks of serious diseases, but methods for investigating such quantitative differences in animals are limited. Accordingly, we have developed a procedure for changing the expression in mice of chosen genes over a 100-fold range while retaining their chromosomal location and transcriptional controls. To develop the procedure, we first dissected the effects in embryonic stem (ES) cells of elements within and downstream of the 3' untranslated region (UTR) of a single copy transgene at the Hprt locus. As expected, protein expression varied with the steady-state level and half-life of the mRNA. The rank order of expression with various tested 3' regions is the same in ES cells, and in cardiomyocytes and trophoblastocytes derived from them. In mice having two functionally different native genes with modified 3'UTRs, the desired expression was obtained.

3' Untranslated Regions↗

PubMed2004

Reduced high serum hepatocyte growth factor levels after successful cardioversion in patients with atrial fibrillation.

1. Serum hepatocyte growth factor (HGF) is considered to be a potent marker of vascular endothelial injury. The present study was designed to examine serum HGF levels in atrial fibrillation and after successful direct current (DC) cardioversion. 2. We measured serum HGF levels before and 7 days and 1 month after DC cardioversion in 39 patients with atrial fibrillation in whom sinus rhythm was maintained for at least 7 days after DC cardioversion and in 30 age- and sex-matched normal control subjects with sinus rhythm. We also measured acetylcholine-induced changes in forearm blood flow (FBF) using venous occlusive plethysmography in 10 patients. 3. Serum HGF levels were significantly higher in the atrial fibrillation patients (both lone atrial fibrillation and with underlying heart disease) than in the controls (0.16 +/- 0.07 vs 0.10 +/- 0.04 ng/mL; P < 0.001). Seven days after successful DC cardioversion, the patients' serum HGF levels had decreased significantly (0.16 +/- 0.07 vs 0.12 +/- 0.06 ng/mL; P < 0.05) and in the 24 patients maintaining sinus rhythm 1 month after DC cardioversion, serum HGF levels decreased to control values (0.10 +/- 0.08 ng/mL at 1 month). Serum HGF levels of the 15 patients who had relapsed into atrial fibrillation 1 month after DC cardioversion tended to decrease 7 days after DC cardioversion, but increased again 1 month after DC cardioversion. Percentage changes in FBF between baseline and the highest dose of acetylcholine before and after DC cardioversion were 180 +/- 98 and 323 +/- 196%, respectively (P = 0.0051). The rate of increase in FBF at the highest dose of acetylcholine between before and after DC cardioversion correlated negatively with the rate of decrease in serum HGF levels between before and after DC cardioversion (r = -0.837; P = 0.0025). 4. This study is the first to demonstrate that serum HGF levels increase in atrial fibrillation and decrease after successful DC cardioversion. This may reflect the fact that atrial fibrillation induces vascular endothelial injury.

Atrial Fibrillation↗

PubMed2004

Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma.

Peroxisome proliferator-activated receptor gamma (PPARgamma), the molecular target of a class of insulin sensitizers, regulates adipocyte differentiation and lipid metabolism. A dominant negative P467L mutation in the ligand-binding domain of PPARgamma in humans is associated with severe insulin resistance and hypertension. Homozygous mice with the equivalent P465L mutation die in utero. Heterozygous mice grow normally and have normal total adipose tissue weight. However, they have reduced interscapular brown adipose tissue and intra-abdominal fat mass, and increased extra-abdominal subcutaneous fat, compared with wild-type mice. They have normal plasma glucose levels and insulin sensitivity, and increased glucose tolerance. However, during high-fat feeding, their plasma insulin levels are mildly elevated in association with a significant increase in pancreatic islet mass. They are hypertensive, and expression of the angiotensinogen gene is increased in their subcutaneous adipose tissues. The effects of P465L on blood pressure, fat distribution, and insulin sensitivity are the same in both male and female mice regardless of diet and age. Thus the P465L mutation alone is sufficient to cause abnormal fat distribution and hypertension but not insulin resistance in mice. These results provide genetic evidence for a critical role for PPARgamma in blood pressure regulation that is not dependent on altered insulin sensitivity.

Adipose Tissue↗

PubMed2003

PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.

A well balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure, which is typically achieved by proper physical exercise, is most effective against obesity and diabetes mellitus. Recently, peroxisome proliferator-activated receptor (PPAR) gamma, a member of the nuclear receptor, and its cofactors have been shown to be involved in lipid metabolism and in the control of energy expenditure. Here we show that PPARgamma coactivator 1 (PGC-1) beta functions as ERRL1 (for ERR ligand 1), which can bind and activate orphan ERRs (estrogen receptor-related receptors) in vitro. Consistently, PGC-1beta/ERRL1 transgenic mice exhibit increased expression of the medium-chain acyl CoA dehydrogenase, a known ERR target and a pivotal enzyme of mitochondrial beta-oxidation in skeletal muscle. As a result, the PGC-1beta/ERRL1 mice show a state similar to an athlete; namely, the mice are hyperphagic and of elevated energy expenditure and are resistant to obesity induced by a high-fat diet or by a genetic abnormality. These results demonstrate that PGC-1beta/ERRL1 can function as a protein ligand of ERR, and that its level contributes to the control of energy balance in vivo, and provide a strategy for developing novel antiobesity drugs.

Amino Acid Sequence↗