Publications by authors named "C T Azuma"

180 Publications

Development of Methods for Convergent Synthesis of Chloroalkene Dipeptide Isosteres and Its Application.

J Org Chem 2021 04 18;86(7):5091-5101. Epub 2021 Mar 18.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Chiyoda-ku, Tokyo 101-0062, Japan.

Improved methods of convergent synthesis for peptidomimetic utilizing a chloroalkene dipeptide isostere (CADI) are reported. In this synthesis, Fmoc- or Boc-protected carboxylic acids can be produced from - and -terminal analogues corresponding to each amino acid starting material via an Evans aldol reaction, followed by a [3.3] sigmatropic rearrangement utilizing the Ichikawa allylcyanate rearrangement reaction. With this strategy, an Fmoc-protected CADI can be directly applied for solid-phase peptide synthesis. Using this approach, we have also identified the CADI-containing [-Lys-Leu-Val-Phe-Phe-] peptidomimetic, which is a superior inhibitor of amyloid-β aggregation than the parent peptide.
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http://dx.doi.org/10.1021/acs.joc.0c03019DOI Listing
April 2021

A Prospective, Open-Label Short-Term Pilot Study on Modification of the Skin Hydration Status During Treatment With a Sodium-Glucose Cotransporter-2 Inhibitor.

Diabetes Ther 2021 Jan 27;12(1):431-440. Epub 2020 Oct 27.

Department of Diabetes and Endocrinology, Kusatsu General Hospital, 1660 Yabase, Kusatsu, Shiga, 525-8585, Japan.

Introduction: Various types of skin lesions with pruritus have been reported in participants of Asian clinical trials on sodium-glucose cotransporter-2 (SGLT2) inhibitors. The aim of this study was to determine whether the diuretic effect of a SGLT2 inhibitor could modify skin hydration status in patients with type 2 diabetes mellitus.

Methods: A prospective, short-term, open-label, two-parallel-arm, pilot study was conducted. Eligible patients were assigned to either a SGLT2 inhibitor (50 mg ipragliflozin once daily) group or to a dipeptidyl peptidase-4 inhibitor (50 mg sitagliptin once daily) group (control). The biophysical characteristics of the skin were measured and blood chemistry tests were run in all participants 1 day prior to medication initiation (pre-treatment values) and 14 days thereafter (post-treatment values).

Results: Fourteen patients were enrolled in the study, of whom eight were in the ipragliflozin group and six in the sitagliptin group. Compared to the pre-treatment values, the glycated hemoglobin (HbA1c) levels were slightly but significantly reduced in the ipragliflozin group (p = 0.02), but the changes in HbA1c from the pre-treatment to post-treatment time points did not significantly differ between the two treatment groups. Serum 3-hydroxy butyrate levels were significantly higher in the ipragliflozin group than in the sitagliptin group (p < 0.02). Neither electrical capacitance nor electrical conductance of the stratum corneum (SC), parameters that reflect skin water content, was reduced by 14 days of ipragliflozin treatment; similarly, no changes in these parameters were found in the sitagliptin control group. There was also no difference in the changes in water barrier function of the SC between the two treatment groups. There was a significant linear correlation (p < 0.01) in skin water content at pre-treatment and that 14 days after treatment with each drug, respectively.

Conclusion: Ipragliflozin treatment for 14 days did not significantly affect the skin hydration status in patients with well-controlled type 2 diabetes mellitus.
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http://dx.doi.org/10.1007/s13300-020-00950-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843859PMC
January 2021

Observation of p.R4810K, a Polymorphism of the Mysterin Gene, the Susceptibility Gene for Moyamoya Disease, in Two Female Japanese Diabetic Patients with Familial Partial Lipodystrophy 1.

Intern Med 2020 15;59(20):2529-2537. Epub 2020 Oct 15.

DNA Chip Research Inc., Japan.

Mysterin, which was recently shown to play an important role in maintaining cellular fat storage, has been identified to be the susceptibility gene for moyamoya disease (MMD). We encountered some female Japanese patients with partial lipodystrophy and MMD-like vascular lesions. This prompted us to examine whether mysterin variants may be present in these patients. We identified a mysterin variant, p.R4810K in two patients with MMD-like vascular lesions, who may fit the category of familial partial lipodystrophy (FPLD) 1. Our cases suggest the possibility that p.R4810K, in addition to atherogenic risk factors, might thus play a role in the development of atherosclerotic lesions in patients with FPLD1 and p.R4810K.
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http://dx.doi.org/10.2169/internalmedicine.4042-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662064PMC
February 2021

Clinical characteristics in two patients with partial lipodystrophy and Type A insulin resistance syndrome due to a novel heterozygous missense mutation in the insulin receptor gene.

Diabetes Res Clin Pract 2019 Jun 16;152:79-87. Epub 2019 May 16.

Division of Endocrinology and Metabolism, Jichi Medical University 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.

Aims: The present report aimed to clarify the clinical characteristics in a girl at the age of 12 and her mother with partial lipodystrophy and Type A insulin resistance syndrome.

Methods: We examined fat distribution in the patients using dual-energy X-ray absorptiometry, magnetic resonance imaging, and computed tomography. We performed genetic analysis to examine the causal gene for lipodystrophy and insulin resistance.

Results: Both patients had partial lipodystrophy and a novel heterozygous missense mutation (Asn → Lys) in the insulin receptor gene. Because Asn in the catalytic loop is conserved in all protein kinases, this mutation was thought to impair insulin receptor function. By whole-exome sequencing, we found the proband had neither mutations in candidate genes known to be associated with familial partial lipodystrophy nor novel likely candidate causal genes. Taken together, we thought that fat loss in these two patients might be caused by insulin receptor dysfunction. The proband had amenorrhea due to polycystic ovary syndrome. Her menstruation improved, as fat loss was restored during adolescence. This might be caused by improving insulin resistance due to increased levels of leptin and fat mass.

Conclusions: This case might help to understand the mechanisms insulin receptor dysfunction that cause lipodystrophy.
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http://dx.doi.org/10.1016/j.diabres.2019.04.034DOI Listing
June 2019

Long-term effects of maternal separation coupled with social isolation on reward seeking and changes in dopamine D1 receptor expression in the nucleus accumbens via DNA methylation in mice.

Neurosci Lett 2017 02 19;641:33-39. Epub 2017 Jan 19.

Department of Anatomy and Cell Biology, Nara Medical University, Kashihara, Nara, 634-8521, Japan. Electronic address:

Early-life stress has long-lasting effects on the stress response, emotions, and behavior throughout an individual's life. Clinical reports have demonstrated that child abuse victims exhibit impairments in reward-associated behavior; yet, the mechanism for this effect remains unclear. Maternal separation (MS) or MS coupled with social isolation (SI) (MS+SI) is widely used as a model for early-life stress in rodent studies. We employed mice subjected to MS+SI to clarify the long-term effect of early-life stress on reward-seeking involving palatable foods by a conditioned place-preference (CPP) paradigm. Prior MS+SI experience decreased exploration time in a chocolate-paired compartment in adult female mice, but not in male mice. We then focused on the mesolimbic dopamine pathway associated with reward-seeking behavior and measured both mRNA and protein levels of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and dopamine D1 and D2 receptors in the nucleus accumbens (NAc). MS+SI female mice had significantly lower D1 receptor mRNA and protein levels than controls, whereas the expression of TH and the D2 receptor was similar in the 2 groups. All mRNA and protein levels were unchanged in MS+SI male mice. When attempting to elucidate the mechanism underlying downregulation of the D1 receptor in the NAc of MS+SI females, we found hypermethylation of the Drd1a promoter region. These results suggest that early-life stress affects reward-seeking behavior in female mice, which may be associated with the downregulation of D1 receptor in the NAc via epigenetic modification of its promoter region.
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http://dx.doi.org/10.1016/j.neulet.2017.01.025DOI Listing
February 2017
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