Ability of NAD and Sirt1 to epigenetically suppress albuminuria.

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.

Successful healing of aneurysmal false lumen using a second-generation drug-eluting stent in spontaneous coronary artery dissection: a case report.

BACKGROUND: According to 2023 ESC Guideline, conservative medical management is generally recommended for the treatment of spontaneous coronary artery dissection (SCAD) except for patients with signs of ongoing myocardial ischemia. However, in some cases, invasive treatment (coronary artery bypass graft surgery or percutaneous coronary intervention (PCI)) is performed because of the progression of aneurysm in SCAD. Although there is no established strategy for the management of coronary aneurysm in SCAD, we report a case of successful healing of aneurysmal false lumen (AFL) using a second-generation drug-eluting stent (DES) in SCAD. CASE PRESENTATION: A 44-year-old woman without any cardiovascular risk factors was transferred to our hospital due to inferior myocardial infarction. Coronary angiography (CAG) showed multiple SCADs in the coronary artery. We performed PCI to the distal right coronary artery (RCA) because the RCA showed severe stenosis (99%) with bradycardia. Six days after the first PCI, SCAD relapsed in the mid left anterior descending artery (LAD). Furthermore, AFL was observed by intravascular ultrasound imaging. To avoid enlargement of the AFL and progression of the dissection toward the proximal site of the LAD, we performed PCI to the mid LAD to seal the entry tear of the dissection using a second-generation DES. CAG revealed that the AFL in the mid LAD completely diminished at 1 year after PCI. CONCLUSIONS: The implantation of a second-generation DES might be one of therapeutic options for sealing AFL in SCAD patients.

Clinical Outcomes of Drug-Eluting Balloon for In-Stent Restenosis Based on the Number of Metallic Layers.

BACKGROUND: This study assesses clinical outcomes after drug-eluting balloon treatment for recurrent in-stent restenosis lesions based on the number of metallic layers. METHODS AND RESULTS: We enrolled 304 consecutive patients (333 lesions) treated with percutaneous coronary intervention using drug-eluting balloon for in-stent restenosis lesions between March 2014 and June 2015. Per the number of stent layers previously implanted to the lesion, the patients were categorized into 3 groups, 1 stent layer (1L), 166 patients; 2 stent layers (2L), 87 patients; and ≥3 stent layers (≥3L), 51 patients. The end points were major adverse cardiovascular events (MACE), including cardiac death, target lesion revascularization, myocardial infarction, and definite or probable stent thrombosis. No significant differences were observed in patients' baseline characteristics among the groups. The 1-year MACE and target lesion revascularization rates were significantly higher in the ≥3L group than those in the 1L and 2L groups (MACE: 1L, 16.9%; 2L, 16.1%; and ≥3L, 43.1%, P<0.01; target lesion revascularization: 1L, 14.5%; 2L, 14.9%; and ≥3L, 41.2%, P<0.01). The multivariable Cox regression analysis revealed that the number of metallic layers (≥3L compared with 1L; hazard ratio, 3.17; [95% CI, 1.75-5.76]; P<0.01 and hemodialysis [hazard ratio, 2.21; (95% CI, 1.12-4.36); P=0.02]) were independent predictors for MACE. No significant differences were observed in the occurrence of cardiac death among the groups ( P=0.34). CONCLUSIONS: Seemingly, drug-eluting balloon is less effective for ≥3L in-stent restenosis lesions. Hemodialysis and in-stent restenosis with the number of metallic layers are independent predictors for MACE.

Pharmacological characterization of FR194921, a new potent, selective, and orally active antagonist for central adenosine A1 receptors.

Adenosine A1 receptors in the brain are believed to play an important role in brain functioning. We have discovered a novel adenosine A1 receptor antagonist, FR194921 (2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone), and characterized the pharmacological activity in the present study. FR194921 showed potent and selective affinity for the adenosine A1 receptor without affinity for A2A and A3 receptors and did not show any species differences in binding affinity profile among human, rat, and mouse. Pharmacokinetic study in rats revealed that FR194921 was orally active and highly brain penetrable. Oral administration of FR194921 dose-dependently ameliorated the hypolocomotion induced by the A1 receptor agonist N6-cyclopentyladenosine in rats, indicating this compound exerts A1-antagonistic action in vivo. In the passive avoidance test, scopolamine (1 mg/kg)-induced memory deficits were significantly ameliorated by FR194921 (0.32, 1 mg/kg). In two animal models of anxiety, the social interaction test and elevated plus maze, FR194921 showed specific anxiolytic activity without significantly influencing general behavior. In contrast, FR194921 did not show antidepressant activity even at a dose of 32 mg/kg in the rat forced swimming test. These results indicate that the novel, potent, and selective adenosine A1 receptor antagonist FR194921 exerts both cognitive-enhancing and anxiolytic activity, suggesting the therapeutic potential of this compound for dementia and anxiety disorders.

Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effect and extrapyramidal side effects: comparison with risperidone and chlorpromazine.

RATIONALE: Quetiapine, an atypical neuroleptic, has beneficial antipsychotic effects in schizophrenic patients, but with a lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. While typical antipsychotics are often switched to atypical agents when adverse effects become limiting, there is little preclinical information to support this strategy, both in terms of efficacy and side effects. OBJECTIVES: The antipsychotic effects and EPS during concomitant administration of quetiapine with haloperidol, a typical antipsychotic agent, were evaluated in mice and compared with chlorpromazine and risperidone. METHODS: We first investigated the antipsychotic effects and EPS liability of quetiapine, risperidone, chlorpromazine, and haloperidol when administered alone to select optimal doses for subsequent combination studies. The second study was designed to evaluate the antipsychotic efficacy and EPS profile of concomitant administration of quetiapine, risperidone, or chlorpromazine with haloperidol. Antipsychotic effects were evaluated with the methamphetamine-induced hyperlocomotion test, and EPS liability was evaluated in a catalepsy-induction model. RESULTS: Quetiapine, risperidone, chlorpromazine, and haloperidol dose-dependently reduced methamphetamine-induced hyperlocomotion, with ED50 values of 5.6, 0.020, 1.8, 0.035 mg/kg, respectively. In the catalepsy test, quetiapine only weakly induced catalepsy at the highest dose of 100 mg/kg, whereas risperidone, chlorpromazine, and haloperidol dose-dependently induced catalepsy with ED50 values of 0.25, 4.6, and 0.10 mg/kg, respectively. While the combination of quetiapine (6 mg/kg) and haloperidol (0.04 mg/kg) significantly reduced methamphetamine-induced hyperlocomotion in comparison with haloperidol alone, quetiapine (10, 32 mg/kg) plus haloperidol did not potentiate the cataleptogenic activity of haloperidol. In contrast, risperidone (0.1, 0.32 mg/kg) or chlorpromazine (3.2 mg/kg) significantly augmented catalepsy induced by haloperidol. Catalepsy induced by co-administration of quetiapine (10 mg/kg) and haloperidol (0.1 mg/kg) was significantly potentiated by WAY100635, a 5-HT1A antagonist, and catalepsy induced by co-administration of risperidone (0.1 mg/kg) and haloperidol (0.1 mg/kg) was significantly antagonized by 8-OH-DPAT, a 5-HT1A agonist. CONCLUSION: The present study demonstrated that the combined administration of quetiapine with haloperidol did not aggravate EPS, possibly because of its affinity for 5-HT1A receptors. This finding may have the clinical implication that quetiapine could provide a successful regimen in switching from typical antipsychotic agents in the symptom management of schizophrenia, or even in adjunctive therapy with other antipsychotic agents.