No abstract

No abstract

No abstract

No abstract

The ten-eleven translocation (TET) protein family, consisting of three isoforms (TET1/2/3), have been found in mammalian cells and have a crucial role in 5-methylcytosine demethylation in genomic DNA through the catalysis of oxidation reactions assisted by 2-oxoglutarate (2OG). DNA methylation/demethylation contributes to the regulation of gene expression at the transcriptional level, and recent studies have revealed that TET1 is highly elevated in malignant cells of various diseases and related to malignant alteration. TET1 inhibitors based on a scaffold of thioether macrocyclic peptides, which have been discovered by the random nonstandard peptide integrated discovery (RaPID) system, are reported. The affinity-based selection was performed against the TET1 compact catalytic domain (TET1CCD) to yield thioether macrocyclic peptides. These peptides exhibited inhibitory activity of the TET1 catalytic domain (TET1CD), with an IC value as low as 1.1 μm. One of the peptides, TiP1, was also able to inhibit TET1CD over TET2CD with tenfold selectivity, although it was likely to target the 2OG binding site; this provides a good starting point to develop more selective inhibitors.

No abstract

Aim To examine the effects of 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods In this multicenter, prospective, randomized, open-label, blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and hemoglobin A1C (HbA1c) of 6.0%—10.0% (42—86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up for 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. Results A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 (95% CI, -0.0155–0.0182) mm and 0.0015 (95% CI, -0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of -0.0001 mm (95% CI, -0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups (-0.1% [95% CI, -0.2–0.1]; P = 0.359). Conclusions Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

Direct observation of sulfur sites for sulfur-containing compounds (cysteine and its oxidative derivatives) on ferrite nanoparticles (FP) was performed by X-ray adsorption near edge structure (XANES) measurements. XANES spectra of cysteine derivatives conjugated with FP indicated that redox reactions occurred on the FP surface. Cysteine was completely oxidized to cystine and cysteinesulfinic acid and cysteic acid were partially reduced. These studies revealed that the FP surface should possess both an oxidation and reduction reactive center for sulfur-containing functional groups.