齋藤 邦明

AIMS: The global distribution of lipoprotein(a) [Lp(a)] levels varies due to racial and ethnic differences. However, the clinical relevance of Lp(a) levels in Japanese patients has not been fully explored. METHODS: We investigated the association of Lp(a) levels, the Suita score, and the presence of high-risk plaque (HRP) as well as that of ≥ 50% stenosis, quantitative plaque volume, and the value of coronary artery calcium score in coronary computed tomographic angiography (CCTA), among 272 Japanese patients (mean age: 65 years) in whom serum Lp(a) levels were measured due to suspected coronary artery disease. HRP was defined as positive remodeling and/or low attenuation. Plaque volume was quantified as the percent plaque volume. RESULTS: HRP was identified in 33 (12.1%) patients. The prevalence of HRP, ≥ 50% stenosis, and percent plaque volume progressively increased with higher Lp (a) levels and Suita scores. In multivariate analyses, Lp(a) and the Suita score independently predicted HRP when assessed as continuous (p = 0.02, p＜0.001, respectively) or categorical variables (p = 0.005, p = 0.007, respectively). Patients in the highest tertile of Lp(a) and classified as high- or intermediate-risk by the Suita score had the highest HRP risk, whereas those in the lower 2 tertiles and low-risk group had the lowest. Incorporating Lp(a) into the Suita score improved the prediction of HRP beyond the Suita score alone (p = 0.005). CONCLUSIONS: The combinatorial value of assessing Lp(a) levels and Suita score may provide useful insight regarding Japanese patients undergoing CCTA for the prediction of HRP.

BACKGROUND: Cisplatin-induced nephrotoxicity (CIN) is a major dose-limiting adverse event that can lead to both acute and chronic kidney injury. The formation of thiol-cisplatin conjugates within renal tubular cells has been implicated as a key mechanism underlying CIN. Flopropione is an inhibitor of cysteine conjugate β-lyase 1, an enzyme that catalyzes the formation of the thiol-cisplatin conjugate, which might prevent CIN. OBJECTIVE: We designed a clinical trial to evaluate the safety of flopropione in patients receiving cisplatin-based chemotherapy and explore its efficacy in preventing CIN. METHODS: This is a phase 1 and 2a, single-center, randomized, open-label trial conducted in patients undergoing cisplatin therapy. Participants are randomized in a 5:2 ratio per cohort to receive either flopropione or no treatment. On the day of cisplatin administration, the flopropione group receives oral flopropione twice daily (80 mg in cohort 1, 160 mg in cohort 2, and 240 mg in cohort 3). On the following day, all cohorts receive 3 doses of 80 mg of oral flopropione. A step-up dose escalation design is adopted, progressing from cohort 1 to 3 after confirming safety at each level. The primary end point is the safety of flopropione use in combination with cisplatin; the secondary end points include changes in the levels of urinary biomarkers of nephrotoxicity such as neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1. Blood and urine samples are collected within 48 hours before cisplatin administration and at 24 hours, 48 hours, and 1 week after its initiation for safety and efficacy assessments. RESULTS: The first participant was registered in July 2024. As of January 2026, participant registration is ongoing. The final participant will complete the study by March 2026. Publication of results is expected by March 2027. CONCLUSIONS: This study is expected to contribute to advances in preventive strategies for CIN by providing evidence that inhibition of cysteine conjugate β-lyase 1 by flopropione may attenuate CIN. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs041220021; https://jrct.mhlw.go.jp/en-latest-detail/jRCTs041220021. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/87907.

Abstract Background and Purpose Lifestyle is closely related to major depressive disorder (MDD). Given the growing focus on the impact of diet on mental health, this study examined how dietary habits affect the pathophysiology of MDD. Experimental Approach Health check‐up data were analysed. Mice received sucrose under chronic unpredictable mild stress (CUMS) and were evaluated by behavioural, neurochemical and metabolic analysis. Key Results Health check‐up data showed increased sucrose intake in MDD patients. When mice received sucrose under CUMS, hyperactivity and aggression were attenuated, although social deficits or behavioural despair induced by CUMS persisted, and recognition memory was impaired. The behavioural changes were associated with dysfunction of the locus coeruleus‐prefrontal cortex circuit, caused by impaired noradrenaline release due to presynaptic α ₂ ‐adrenoceptor upregulation, and postsynaptic α ₁ ‐adrenoceptor and β ₁ ‐adrenoceptor downregulation. α ₂ ‐Adrenoceptor antagonism by atipamezole rescued behavioural changes induced by sucrose intake under CUMS, whereas α ₂ ‐adrenoceptor agonism by guanfacine in CUMS mice mimicked these behavioural changes. Among the antidepressants, mirtazapine effectively increased noradrenaline release and rescued behavioural changes induced by sucrose intake under CUMS. Sucrose intake under CUMS induced peripheral hyperglycaemia and dysregulation of central glucose metabolism. Glucose transporter inhibition by phloretin rescued behavioural changes induced by sucrose intake under CUMS. Intracerebroventricular and systemic streptozotocin administration reproduced these behavioural changes and α ₂ ‐adrenoceptor upregulation. Conclusions and Implications Our findings suggest that the observed behavioural changes are associated with dysfunction of the noradrenergic α ₂ ‐adrenoceptor system induced by impaired glucose metabolism. These insights targeting the noradrenergic‐metabolic axis might be a new strategy for sugar‐induced depression subtypes.