Structure-Activity Relationship Analysis of Fluoxetine for Suppression of Inflammatory Cytokine Production.

There is accumulating evidence that selective serotonin reuptake inhibitors (SSRIs), clinically used as antidepressants, have a beneficial effect on inflammatory diseases such as coronavirus disease 2019 (COVID-19). We previously compared the inhibitory effects of five U.S. Food and Drug Administration (FDA)-approved SSRIs on the production of an inflammatory cytokine, interleukin-6 (IL-6), and concluded that fluoxetine (FLX) showed the most potent anti-inflammatory activity. Here, we investigated the structure-activity relationship of FLX for anti-inflammatory activity towards J774.1 murine macrophages. FLX suppressed IL-6 production induced by the TLR3 agonist polyinosinic-polycytidylic acid (poly(I : C)) with an IC50 of 4.76 µM. A derivative of FLX containing chlorine instead of the methylamino group lacked activity, suggesting that the methylamino group is important for the anti-inflammatory activity. FLX derivatives bearing an N-propyl or N-(pyridin-3-yl)methyl group in place of the N-methyl group exhibited almost the same activity as FLX. Other derivatives showed weaker activity, and the N-phenyl and N-(4-trifluoromethyl)benzyl derivatives were inactive. The chlorine-containing derivative also lacked inhibitory activity against TLR9- or TLR4-mediated IL-6 production. These derivatives showed similar structure-activity relationships for TLR3- and TLR9-mediated inflammatory responses. However, the activities of all amino group-containing derivatives against the TLR4-mediated inflammatory response were equal to or higher than the activity of FLX. These results indicate that the substituent at the nitrogen atom in FLX strongly influences the anti-inflammatory effect.

Real-world clinical evidence of oral semaglutide on metabolic abnormalities in subjects with type 2 diabetes: a multicenter retrospective observational study (the Sapporo-Oral SEMA study).

Oral semaglutide has potent anti-hyperglycemic efficacy in phase III trials. However, the complicated dosing instructions hamper to use this drug; therefore, we evaluated the efficacy and safety of oral semaglutide in subjects with type 2 diabetes in a real-world clinical setting. In this multi-center retrospective observational study, we analyzed subjects with type 2 diabetes newly treated with an oral semaglutide for >6 months at four medical centers located in Sapporo, Japan. The changes in glycated hemoglobin, body weight, and other metabolic parameters were evaluated and any adverse event leading to semaglutide discontinuation were recorded from February 2021 to December 2022. This study was registered with the University Hospital Medical Information Network Center (UMIN000050583). Of 543 subjects who met the inclusion criteria, data for 434 subjects (age 55.5 ± 12.6 years; body mass index 29.6 ± 6.0 kg/m2) were analyzed. After a 6 months of observation period, semaglutide 3 mg, 7 mg, or 14 mg was used by 55 (12.7%), 241 (55.5%), and 138 (31.8%) of subjects, respectively. Both glycated hemoglobin and body weight significantly improved: 7.65 ± 1.11% to 6.88 ± 0.91% (p < 0.001) and 80.2 ± 19.2 kg to 77.6 ± 19.2 kg (p < 0.001), respectively. Efficacy was also confirmed in the subgroup switched from other anti-hyperglycemic agents, including dipeptidyl peptidase-4 inhibitors. In total, 154 subjects had symptomatic gastrointestinal symptoms and 39 (7.2%) were discontinued semaglutide due to the adverse events. None of the participants experienced severe hypoglycemic events. Oral semaglutide in subjects with type 2 diabetes improved glycemic control and body weight in a real-world clinical setting.

Design and Synthesis of Poly(2,2'-Bipyridyl) Ligands for Induction of Cell Death in Cancer Cells: Control of Anticancer Activity by Complexation/Decomplexation with Biorelevant Metal Cations.

Chelation therapy is a medical procedure for removing toxic metals from human organs and tissues and for the treatment of diseases by using metal-chelating agents. For example, iron chelation therapy is designed not only for the treatment of metal poisoning but also for some diseases that are induced by iron overload, cancer chemotherapy, and related diseases. However, the use of such metal chelators needs to be generally carried out very carefully, because of the side effects possibly due to the non-specific complexation with intracellular metal cations. Herein, we report on the preparation and characterization of some new poly(bpy) ligands (bpy: 2,2'-bipyridyl) that contain one-three bpy ligand moieties and their anticancer activity against Jurkat, MOLT-4, U937, HeLa S3, and A549 cell lines. The results of MTT assays revealed that the tris(bpy) and bis(bpy) ligands exhibit potent activity for inducing the cell death in cancer cells. Mechanistic studies suggest that the main pathway responsible for the cell death by these poly(bpy) ligands is apoptotic cell death. It was also found that the anticancer activity of the poly(bpy) ligands could be controlled by the complexation (anticancer activity is turned OFF) and decomplexation (anticancer activity is turned ON) with biorelevant metal cations. In this paper, these results will be described.

Optical Resolution of Carboxylic Acid Derivatives of Homoleptic Cyclometalated Iridium(III) Complexes via Diastereomers Formed with Chiral Auxiliaries.

We report on a facile method for the optical resolution of cyclometalated iridium(III) (Ir(III)) complexes via diastereomers formed with chiral auxiliaries. The racemic carboxylic acids of Ir(III) complexes (fac-4 (fac-Ir(ppyCO2H)3 (ppy: 2-phenylpyridine)), fac-6 (fac-Ir(tpyCO2H)3 (tpy: 2-(4'-tolyl)pyridine)), and fac-13 (fac-Ir(mpiqCO2H)3 (mpiq: 1-(4'-methylphenyl)isoquinoline))) were converted into the diastereomers, Δ- and Λ-forms of fac-9 (from fac-6), fac-10 (from fac-4), fac-11 (from fac-6), and fac-14 (from fac-13), respectively, by the condensation with (1R,2R)-1,2-diaminocyclohexane or (1R,2R)-2-aminocyclohexanol. The resulting diastereomers were separated by HPLC (with a nonchiral column) or silica gel column chromatography, and their absolute stereochemistry was determined by X-ray single-crystal structure analysis and CD (circular dichroism) spectra. Spectra of all diastereomers of the Ir(III) complexes are reported. Hydrolysis of the ester moieties of Δ- and Λ-forms of fac-10, fac-11, and fac-14 gave both enantiomers of the corresponding carboxylic acid derivatives in the optically pure forms, Δ-fac and Λ-fac-4, -6, and -13, respectively.

Development of Wireless Power-Transmission-Based Photodynamic Therapy for the Induction of Cell Death in Cancer Cells by Cyclometalated Iridium(III) Complexes.

Photodynamic therapy (PDT), a noninvasive method for cancer therapy, involves the generation of reactive oxygen species (ROS) by the photochemical excitation of photosensitizers (PSs) to induce cell death in cancer cells. A variety of PS including porphyrin derivatives and metal complexes such as iridium (Ir) complexes have been reported. In clinical trials, red-near infrared (NIR) light (650-900 nm) is preferred for the excitation of PSs due to its deeper penetration into tissues compared with visible light (400-500 nm). To overcome this limitation, we established a PDT system that uses cyclometalated iridium(III) (Ir(III)) complexes that are excited with blue light in the wireless power transmission (WPT) system. To achieve this, we developed a light-emitting diode (LED) light device equipped with a receiver coil that receives electricity from the transmitter coil through magnetic resonance coupling. The LEDs in the receiving device use blue light (470 nm) to irradiate a given Ir(III) complex and excite triplet oxygen (3O2) to singlet oxygen (1O2) which induces cell death in HeLa S3 cells (human cervical carcinoma cells). The results obtained in this study suggest that WPT-based PDT represents a potentially new method for the treatment of tumors by a non-battery LED, which are otherwise difficult to treat by previous PDT systems.

Regulator of Awn Elongation 3, an E3 ubiquitin ligase, is responsible for loss of awns during African rice domestication.

Two species of rice have been independently domesticated from different ancestral wild species in Asia and Africa. Comparison of mutations that underlie phenotypic and physiological alterations associated with domestication traits in these species gives insights into the domestication history of rice in both regions. Asian cultivated rice, Oryza sativa, and African cultivated rice, Oryza glaberrima, have been modified and improved for common traits beneficial for humans, including erect plant architecture, nonshattering seeds, nonpigmented pericarp, and lack of awns. Independent mutations in orthologous genes associated with these traits have been documented in the two cultivated species. Contrary to this prevailing model, selection for awnlessness targeted different genes in O. sativa and O. glaberrima. We identify Regulator of Awn Elongation 3 (RAE3) a gene that encodes an E3 ubiquitin ligase and is responsible for the awnless phenotype only in O. glaberrima. A 48-bp deletion may disrupt the substrate recognition domain in RAE3 and diminish awn elongation. Sequencing analysis demonstrated low nucleotide diversity in a ~600-kb region around the derived rae3 allele on chromosome 6 in O. glaberrima compared with its wild progenitor. Identification of RAE3 sheds light on the molecular mechanism underlying awn development and provides an example of how selection on different genes can confer the same domestication phenotype in Asian and African rice.

Post-complexation Functionalization of Cyclometalated Iridium(III) Complexes and Applications to Biomedical and Material Sciences.

Cyclometalated iridium(III) (Ir(III)) complexes exhibit excellent photophysical properties that include large Stokes shift, high emission quantum yields, and microsecond-order emission lifetimes, due to low-lying metal-to-ligand charge transfer (spin-forbidden singlet-triplet (3MLCT) transition). As a result, analogs have been applied for research not only in the material sciences, such as the development of organic light-emitting diodes (OLEDs), but also for photocatalysts, bioimaging probes, and anticancer reagents. Although a variety of methods for the synthesis and the applications of functionalized cyclometalated iridium complexes have been reported, functional groups are generally introduced to the ligands prior to the complexation with Ir salts. Therefore, it is difficult to introduce thermally unstable functional groups such as peptides and sugars due to the harsh reaction conditions such as the high temperatures used in the complexation with Ir salts. In this review, the functionalization of Ir complexes after the formation of cyclometalated Ir complexes and their biological and material applications are described. These methods are referred to as "post-complexation functionalization (PCF)." In this review, applications of PCF to the design and synthesis of Ir(III) complexes that exhibit blue -red and white color emissions, luminescence pH probes, luminescent probes of cancer cells, compounds that induce cell death in cancer cells, and luminescent complexes that have long emission lifetimes are summarized.

Profiling Differential Effects of 5 Selective Serotonin Reuptake Inhibitors on TLRs-Dependent and -Independent IL-6 Production in Immune Cells Identifies Fluoxetine as Preferred Anti-Inflammatory Drug Candidate.

Excessive proinflammatory cytokine production induced by abnormal activation of Toll-like receptor (TLR) signaling, for example, by SARS-CoV-2 infection, can cause a fatal cytokine storm. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine, used to treat depression, were recently reported to reduce the risk of severe disease in patients with coronavirus disease 2019 (COVID-19), but the mechanisms of the anti-inflammatory effects of SSRIs, and which SSRI would be most suitable as an anti-inflammatory drug, remain unclear. Here, we examined the inhibitory effects of 5 FDA-approved SSRIs, paroxetine, fluoxetine, fluvoxamine, sertraline and escitalopram, on the production of interleukin-6 (IL-6) induced by stimulation with multiple TLR agonists in murine macrophages and dendritic cells, and on the production of cytokines induced by concanavalin A in murine lymphocytes. In J774.1 murine macrophage cells, pretreatment with SSRIs significantly suppressed IL-6 release induced by TLR3 agonist poly(I:C), TLR4 agonist LPS or TLR9 agonist CpG ODN, but did not affect IL-6 release induced by TLR7 agonists imiquimod or resiquimod. In accordance with the results obtained in J774.1 cells, pretreatment with SSRIs also suppressed IL-6 release induced by a TLR3, TLR4 or TLR9 agonist in bone marrow-derived dendritic cells and peritoneal cells of C57BL/6 mice. On the other hand, interestingly, sertraline alone among the SSRIs amplified IL-6 production induced by TLR7 agonists in murine dendritic cells, though not in macrophages. Concanavalin A-induced production of IL-6 or IL-2 in murine lymphocytes was suppressed by SSRIs, suggesting that SSRIs also inhibit TLRs-independent IL-6 production. Since SSRIs suppressed both IL-6 production induced by multiple TLR agonists in macrophages or dendritic cells and TLR-independent IL-6 production in lymphocytes, they are promising candidates for treatment of patients with cytokine storm, which is mediated by overactivation of multiple TLRs in a complex manner, leading to the so-called IL-6 amplifier, an IL-6 overproduction loop. However, the 5 SSRIs examined here all showed different effects. Overall, our results suggest that fluoxetine may be the most promising candidate as an anti-inflammatory drug. An examination of the structural requirements indicated that the N-methyl group of fluoxetine has a critical role in the inhibition of IL-6 production.

Design, synthesis and biological evaluation of 2-pyrrolone derivatives as radioprotectors.

It is known that p53 is an important transcription factor and plays a central role in ionizing radiation (IR)-induced DNA damage responses such as cell cycle arrest, DNA repair and apoptosis. We previously reported that regulating p53 protein is an effective strategy for modulating cell fate by reducing the acute side effects of radiation therapy. Herein, we report on the discovery of STK160830 as a new radioprotector from a chemical library at The University of Tokyo and the design, synthesis and biological evaluation of its derivatives. The radioprotective activity of STK160830 itself and its derivatives that were synthesized in this work was evaluated using a leukemia cell line, MOLT-4 cells as a model of normal cells that express the p53 protein in a structure-activity relationships (SAR) study. The experimental results suggest that a direct relationship exists between the inhibitory effect of these STK160830 derivatives on the expression level of p53 and their radioprotective activity and that the suppression of p53 by STK160830 derivatives contribute to protecting MOLT-4 cells from apoptosis that is induced by exposure to radiation.

Effects of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide on glucose metabolism in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, parallel-group comparison study (the SWITCH-SEMA 2 study).

INTRODUCTION: Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%-9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters. ETHICS AND DISSEMINATION: This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020-013). TRIAL REGISTRATION NUMBER: UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.

Induction of Paraptosis by Cyclometalated Iridium Complex-Peptide Hybrids and CGP37157 via a Mitochondrial Ca2+ Overload Triggered by Membrane Fusion between Mitochondria and the Endoplasmic Reticulum.

We previously reported that a cyclometalated iridium (Ir) complex-peptide hybrid (IPH) 4 functionalized with a cationic KKKGG peptide unit on the 2-phenylpyridine ligand induces paraptosis, a relatively newly found programmed cell death, in cancer cells (Jurkat cells) via the direct transport of calcium (Ca2+) from the endoplasmic reticulum (ER) to mitochondria. Here, we describe that CGP37157, an inhibitor of a mitochondrial sodium (Na+)/Ca2+ exchanger, induces paraptosis in Jurkat cells via intracellular pathways similar to those induced by 4. The findings allow us to suggest that the induction of paraptosis by 4 and CGP37157 is associated with membrane fusion between mitochondria and the ER, subsequent Ca2+ influx from the ER to mitochondria, and a decrease in the mitochondrial membrane potential (ΔΨm). On the contrary, celastrol, a naturally occurring triterpenoid that had been reported as a paraptosis inducer in cancer cells, negligibly induces mitochondria-ER membrane fusion. Consequently, we conclude that the paraptosis induced by 4 and CGP37157 (termed paraptosis II herein) proceeds via a signaling pathway different from that of the previously known paraptosis induced by celastrol, a process that negligibly involves membrane fusion between mitochondria and the ER (termed paraptosis I herein).

Design, Synthesis, and Anticancer Activity of Triptycene-Peptide Hybrids that Induce Paraptotic Cell Death in Cancer Cells.

We report on the design and synthesis of triptycene-peptide hybrids (TPHs), 5, syn-6, and anti-6, which are conjugates of a triptycene core unit with two or three cationic KKKGG peptides (K: lysine and G: glycine) through a C8 alkyl chain. It was discovered that syn-6 and anti-6 induce paraptosis, a type of programmed cell death (PCD), in Jurkat cells (leukemia T-lymphocytes). Mechanistic studies indicate that these TPHs induce the transfer of Ca2+ from the endoplasmic reticulum (ER) to mitochondria, a loss of mitochondrial membrane potential (ΔΨm), tethering of the ER and mitochondria, and cytoplasmic vacuolization in the paraptosis processes.

Do the benefits of sodium-glucose cotransporter 2 inhibitors exceed the risks in patients with type 1 diabetes?

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are well-established means of improving glycemia and preventing cardio-renal events in patients with type 2 diabetes. However, their efficacy and safety have yet to be fully characterized in patients with type 1 diabetes (T1D). We studied patients with T1D who regularly attended one of five diabetes centers and treated with an SGLT2i (ipragliflozin or dapagliflozin) for >52 weeks, and the changes in HbA1c, body mass, insulin dose, and laboratory data were retrospectively evaluated and adverse events (AEs) recorded during December 2018 to April 2021. A total of 216 patients with T1D were enrolled during the period. Of these, 42 were excluded owing to short treatment periods and 15 discontinued their SGLT2i. The mean changes in glycated hemoglobin (HbA1c), body mass, and insulin dose were -0.4%, -2.1 kg, and -9.0%, respectively. The change in HbA1c was closely associated with the baseline HbA1c (p < 0.001), but not with the baseline body mass or renal function. The basal and bolus insulin doses decreased by 18.2% and 12.6%, respectively, in participants with a baseline HbA1c <8%. The most frequent AE was genital infection (2.8%), followed by diabetic ketoacidosis (DKA; 1.4%). None of the participants experienced severe hypoglycemic events. In conclusion, the administration of an SGLT2i in addition to intensive insulin treatment in patients with T1D improves glycemic control and body mass, without increasing the incidence of hypoglycemia or DKA.

Cyclometalated Iridium(III) Complex-Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca2+ Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential.

In our previous paper, we reported that amphiphilic Ir complex-peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca2+)-calmodulin (CaM) complex and induce an overload of intracellular Ca2+, resulting in the induction of non-apoptotic programmed cell death. In this work, we conduct a detailed mechanistic study of cell death induced by ASb-2, a typical example of IPHs, and describe how ASb-2 induces paraptotic programmed cell death in a manner similar to that of celastrol, a naturally occurring triterpenoid that is known to function as a paraptosis inducer in cancer cells. It is suggested that ASb-2 (50 µM) induces ER stress and decreases the mitochondrial membrane potential (ΔΨm), thus triggering intracellular signaling pathways and resulting in cytoplasmic vacuolization in Jurkat cells (which is a typical phenomenon of paraptosis), while the change in ΔΨm values is negligibly induced by celastrol and curcumin. Other experimental data imply that both ASb-2 and celastrol induce paraptotic cell death in Jurkat cells, but this induction occurs via different signaling pathways.

Isorhamnetin Promotes 53BP1 Recruitment through the Enhancement of ATM Phosphorylation and Protects Mice from Radiation Gastrointestinal Syndrome.

Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the suppressive effect against GI syndrome.

A Novel RNA Synthesis Inhibitor, STK160830, Has Negligible DNA-Intercalating Activity for Triggering A p53 Response, and Can Inhibit p53-Dependent Apoptosis.

RNA synthesis inhibitors and protein synthesis inhibitors are useful for investigating whether biological events with unknown mechanisms require transcription or translation; however, the dependence of RNA synthesis has been difficult to verify because many RNA synthesis inhibitors cause adverse events that trigger a p53 response. In this study, we screened a library containing 9600 core compounds and obtained STK160830 that shows anti-apoptotic effects in irradiated wild-type-p53-bearing human T-cell leukemia MOLT-4 cells and murine thymocytes. In many of the p53-impaired cells and p53-knockdown cells tested, STK160830 did not show a remarkable anti-apoptotic effect, suggesting that the anti-apoptotic activity is p53-dependent. In the expression analysis of p53, p53-target gene products, and reference proteins by immunoblotting, STK160830 down-regulated the expression of many of the proteins examined, and the downregulation correlated strongly with its inhibitory effect on cell death. mRNA expression analyses by qPCR and nascent RNA capture kit revealed that STK160830 showed a decreased mRNA expression, which was similar to that induced by the RNA synthesis inhibitor actinomycin D but differed to some extent. Furthermore, unlike other RNA synthesis inhibitors such as actinomycin D, p53 accumulation by STK160830 alone was negligible, and a DNA melting-curve analysis showed very weak DNA-intercalating activity, indicating that STK160830 is a useful inhibitor for RNA synthesis without triggering p53-mediated damage responses.

Lowering of blood pressure and pulse rate by switching from DPP-4 inhibitor to luseogliflozin in patients with type 2 diabetes complicated with hypertension: A multicenter, prospective, randomized, open-label, parallel-group comparison trial (LUNA study).

AIMS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces clinic blood pressure (BP), but the effects on BP circadian rhythm remain unclear. The present study aimed to determine the nighttime antihypertensive effect of SGLT2i compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) in patients with type 2 diabetes and hypertension. MATERIALS AND METHODS: In this randomized, open-label, parallel-group trial, patients treated with DPP-4i were either switched to luseogliflozin 2.5 mg/day (Luseo group;n = 30) or continued DPP-4i (DPP-4i group;n = 26). The patients undertook 24-h ambulatory BP monitoring before and 8 weeks after the group allocation. The primary endpoint was mean change in nighttime systolic BP (SBP). RESULTS: Nighttime SBP, as well as daytime SBP, was significantly reduced in the Luseo group compared with the DPP-4i group (nighttime, -4.0 ± 11.4 vs. 3.6 ± 10.7 mmHg,P = 0.01; daytime, -4.4 ± 10.9 vs. 3.7 ± 11.9 mmHg,P = 0.01). Similarly, nighttimepulse rate(PR) was significantly reduced in the Luseo group (-2.0 ± 4.8 vs. 0.9 ± 4.8 bpm,P = 0.03). The proportion of patients with abnormal BP circadian rhythms (non-dipper pattern plus riser pattern) was significantly lower in the Luseo group (36.6% vs. 56.7%,P < 0.05). CONCLUSIONS: Switching from DPP-4i to luseogliflozin decreased nighttime SBP and PR; moreover, BP circadian rhythm was improved.

Evaluation of sodium orthovanadate as a radioprotective agent under total-body irradiation and partial-body irradiation conditions in mice.

PURPOSE: Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. METHODS: Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. RESULTS: TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. CONCLUSION: Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.