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Biomedical subjects

Hiroshi Tanaka

Publications and source records attributed to Hiroshi Tanaka.

At least 19 recordsLinked to original sources
PubMed2026

Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the senescence-associated secretory phenotype (SASP), including interferon-stimulated genes (ISGs). Here we confirm and extend previous observations that cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of nonproliferating senescent cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver. Further, palbociclib suppresses frailty and improves physical performance of aged mice. These findings demonstrate a role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising target for therapeutic repurposing.

Animals↗
PubMed2025

Nucleosome stability safeguards cell identity, stress resilience and healthy aging.

Nucleosomes are the minimal repeating units of chromatin. Their dynamic assembly and disassembly underpins chromatin organization and genome regulation. However, it remains unclear how intrinsic nucleosome stability contributes to higher-level yet fundamental cellular and organismal properties-such as preservation of cell identity, lineage specification, stress resilience and ultimately healthy aging. To address this, we tested the impact of decreased intrinsic nucleosome stability across multiple cell, tissue and organismal models by introducing histone mutants that weaken histone-histone interactions. While nucleosome instability did not broadly alter global chromatin accessibility, DNA damage, cell proliferation or viability, it impaired lineage-specific gene expression programs, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated the onset of age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations-including environmental, epigenetic and mitotic stress-in human cells and Saccharomyces cerevisiae. These cross-species findings identify nucleosome stability as an evolutionarily conserved epigenetic safeguard that preserves cell identity and stress resilience and supports organismal function and healthy aging.

Journal Article↗
PubMed2007

Mismatch recovery of regional cerebral blood flow and brain temperature during reperfusion after prolonged brain ischemia in gerbils.

BACKGROUND: Recovery of cerebral reperfusion after stroke or cardiac arrest can take a long time. We aimed to identify differences in the postischemic recovery of physiologic parameters between short and prolonged brain ischemia. METHODS: Eighteen Mongolian gerbils were assigned to one of three groups: 5-minute (G5), 15-minute (G15), or 30-minute (G30) ischemia. With the use of our original microspectroscopy system, global ischemic reperfusion was performed. We measured changes in regional cerebral blood flow (r-CBF), microvessel diameter, and brain temperature (BrT) simultaneously. We also monitored somatosensory evoked potentials (SEPs) to evaluate electrophysiologic response. RESULTS: Both G5 and G15 showed concurrent recovery of r-CBF and BrT with hyperemia and hyperthermia, respectively, 10 to 15 minutes after reperfusion. The increase in BrT was <1 degree C and recovered to baseline within 60 minutes after reperfusion. In G30, recovery of r-CBF was significantly delayed relative to that of BrT. The increase in BrT was >2 degrees C, peaking approximately 15 minutes after reperfusion, and then maintained increases of >1 degree C for 120 minutes. SEPs in G5 and G15 showed concomitant recovery with that of r-CBF, whereas SEP recovery in G30 was delayed relative to that of r-CBF, eventually disappearing. All except one of the G30 gerbils died within 24 hours, but all in G5 and G15 survived. CONCLUSIONS: These results suggest that mismatch recovery of r-CBF and BrT after prolonged ischemia initiates metabolic derangement in brain tissue, leading to the electrochemical dysfunction and mortality.

Analysis of Variance↗
PubMed2006

Treatment of difficult cases of systemic-onset juvenile idiopathic arthritis with tacrolimus.

Since a proportion of systemic-onset juvenile idiopathic arthritis (SOJIA) patients continue to require long-term corticosteroid therapy for disease control, an effective and safe therapeutic strategy for controlling the activity of refractory SOJIA remains to be established. We report the efficacy of tacrolimus for the treatment of SOJIA in two patients with refractory SOJIA, one of them showing poor response to cyclosporine A. Tacrolimus might be the treatment of choice in selected patients with refractory systemic-onset juvenile idiopathic arthritis. Further studies to confirm the long-term efficacy and safety of tacrolimus in larger numbers of patients are, however, needed.

Arthritis, Juvenile↗
PubMed2006

Carbohydrate-binding module of a rice endo-beta-1,4-glycanase, OsCel9A, expressed in auxin-induced lateral root primordia, is post-translationally truncated.

We report the cloning of a glycoside hydrolase family (GHF) 9 gene of rice (Oryza sativa L. cv. Sasanishiki), OsCel9A, corresponding to the auxin-induced 51 kDa endo-1,4-beta-glucanase (EGase). This enzyme reveals a broad substrate specificity with respect to sugar backbones (glucose and xylose) in beta-1,4-glycans of type II cell wall. OsCel9A encodes a 640 amino acid polypeptide and is an ortholog of TomCel8, a tomato EGase containing a carbohydrate-binding module (CBM) 2 sequence at its C-terminus. The expression of four rice EGase genes including OsCel9A showed different patterns of organ specificity and responses to auxin. OsCel9A was preferentially expressed during the initiation of lateral roots or subcultured root calli, but was hardly expressed during auxin-induced coleoptile elongation or in seed calli, in contrast to OsCel9D, a KORRIGAN (KOR) homolog. In situ localization of OsCel9A transcripts demonstrated that its expression was specifically up-regulated in lateral root primordia (LRP). Northern blotting analysis showed the presence of a single product of OsCel9A. In contrast, both mass spectrometric analyses of peptide fragments from purified 51 kDa EGase proteins and immunogel blot analysis of EGase proteins in root extracts using two antibodies against internal peptide sequences of OsCel9A revealed that the entire CBM2 region was post-translationally truncated from the 67 kDa nascent protein to generate 51 kDa EGase isoforms. Analyses of auxin concentration and time course dependence of accumulation of two EGase isoforms suggested that the translation and post-translational CBM2 truncation of the OsCel9A gene may participate in lateral root development.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2006

Pulmonary nontuberculous mycobacterial infection caused by Mycobacterium szulgai in a young healthy woman.

A 20-year-old woman with no history of pulmonary disease had no symptom and her chest CT scans demonstrated adhesive small multiple nodules in the bronchial lung biopsy specimen showed epithelioid cell granuloma containing Langhans giant cells, therefore she was diagnosed as pulmonary mycobacteriosis caused by M. szulgai. This is the youngest case of this rare condition occurring in a healthy subject without underlying pulmonary diseases.

Adult↗
PubMed2006

Missing link in the evolution of Hox clusters.

Hox cluster has key roles in regulating the patterning of the antero-posterior axis in a metazoan embryo. It consists of the anterior, central and posterior genes; the central genes have been identified only in bilaterians, but not in cnidarians, and are responsible for archiving morphological complexity in bilaterian development. However, their evolutionary history has not been revealed, that is, there has been a "missing link". Here we show the evolutionary history of Hox clusters of 18 bilaterians and 2 cnidarians by using a new method, "motif-based reconstruction", examining the gain/loss processes of evolutionarily conserved sequences, "motifs", outside the homeodomain. We successfully identified the missing link in the evolution of Hox clusters between the cnidarian-bilaterian ancestor and the bilaterians as the ancestor of the central genes, which we call the proto-central gene. Exploring the correspondent gene with the proto-central gene, we found that one of the acoela Hox genes has the same motif repertory as that of the proto-central gene. This interesting finding suggests that the acoela Hox cluster corresponds with the missing link in the evolution of the Hox cluster between the cnidarian-bilaterian ancestor and the bilaterians. Our findings suggested that motif gains/diversifications led to the explosive diversity of the bilaterian body plan.

Amino Acid Motifs↗
PubMed2006

A new mechanism of methotrexate action revealed by target screening with affinity beads.

Methotrexate (MTX) is the anticancer and antirheumatoid drug that is believed to block nucleotide synthesis and cell cycle by inhibiting dihydrofolate reductase activity. We have developed novel affinity matrices, termed SG beads, that are easy to manipulate and are compatible with surface functionalization. Using the matrices, here we present evidence that deoxycytidine kinase (dCK), an enzyme that acts in the salvage pathway of nucleotide biosynthesis, is another target of MTX. MTX modulates dCK activity differentially depending on substrate concentrations. 1-beta-D-Arabinofuranosylcytosine (ara-C), a chemotherapy agent often used in combination with MTX, is a nucleoside analog whose incorporation into chromosome requires prior phosphorylation by dCK. We show that, remarkably, MTX enhances incorporation and cytotoxicity of ara-C through regulation of dCK activity in Burkitt's lymphoma cells. Thus, this study provides new insight into the mechanisms underlying MTX actions and demonstrates the usefulness of the SG beads.

Amino Acid Sequence↗
PubMed2006

Classification of acute pancreatitis based on retroperitoneal extension: application of the concept of interfascial planes.

OBJECTIVE: This study aimed to provide a classification system for acute pancreatitis by applying the principle that the disease spreads along the retroperitoneal interfascial planes. MATERIALS AND METHODS: Medical records and computed tomography (CT) images of 58 patients with acute pancreatitis treated between 2000 and 2005 were reviewed. The retroperitoneum was subdivided into 10 components according to the concept of interfascial planes. Severity of acute pancreatitis was graded according to retroperitoneal extension into these components. Clinical courses and outcomes were compared with the grades. The prognostic value of our classification system was compared with that of Balthazar's CT severity index (CTSI). RESULTS: Retroperitoneal extension of acute fluid collection was classified into five grades: Grade I, fluid confined to the anterior pararenal space or retromesenteric plane (8 patients); Grade II, fluid spreading into the lateroconal or retrorenal plane (16 patients); Grade III, fluid spreading into the combined interfascial plane (8 patients); Grade IV, fluid spreading into the subfascial plane beyond the interfascial planes (15 patients); and Grade V, fluid intruding into the posterior pararenal space (11 patients). Morbidity and mortality were 92.3% and 38.5% in the 26 patients with Grade IV or V disease, and 21.9% and 0% in the 32 patients with Grade I, II, or III disease. Morbidity and mortality were 86.7% and 33.3% in patients with disease classified "severe" according to the CTSI, and 37.5% and 9.4% in patients with disease classified "mild" or "moderate". CONCLUSION: Classification of acute pancreatitis based on CT-determined retroperitoneal extension is a useful indicator of the disease severity and prognosis without the need for contrast-medium enhanced CT.

Acute Disease↗
PubMed2006

A unique amino acid substitution, T126I, in human genotype C of hepatitis B virus S gene and its possible influence on antigenic structural change.

Amino acid substitutions in the S gene of hepatitis B virus (HBV), especially in the 'a' determinant region, have been suggested to affect the antigenicity of the virus and the clinical outcome of the infected patient. However, no convincing evidence has been presented for this hypothesis, partly because the 3D structure of the S protein has not been determined. Comparative analysis of viral genes offers an approach to testing this hypothesis, as it may reveal signals of natural selection and provide insights into the functional significance of the observed amino acid substitutions. In this study, we analyze HBV S gene sequences obtained from 24 patients infected with HBV genotypes B or C, together with 16 representative viral strains of HBV genotypes A-F retrieved from GenBank. We use phylogenetic methods to infer evolutionary changes among HBV genotypes and to identify amino acid residues potentially under positive selective pressure. Furthermore, we employ the fragment assembly method to predict structural changes in the S protein. The results showed that an amino acid substitution within the 'a' determinant, T126I, was unique to genotype C, may affect the antigenicity of the HBsAg, and may result in poorer clinical outcomes of patients infected with genotype C viral strains. We suggest that an integrated approach of evolutionary comparison and structural prediction is useful in generating hypotheses for further laboratory validation.

Adult↗
PubMed2006

(R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties.

Recent studies have suggested that the alpha7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

Animals↗
PubMed2006

[Genital anomaly].

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Abnormalities, Multiple↗