Biological & pharmaceutical bulletin最新文献

Atherosclerosis is a pathological condition that leads to cardiovascular disease and cerebral infarction. Oxidatively modified low-density lipoprotein (LDL), known as oxidized LDL (oxLDL), is one of the major factors for atherogenesis, because it serves as a ligand for scavenger receptors. We and others developed sensitive methods to measure plasma oxLDL levels in the 1990's, and since then, mounting evidence has accumulated demonstrating the relationship between cardiovascular diseases and oxLDL in vivo. Mechanistic insights into the generation, metabolism, and modified structures of oxLDL in vivo have also been obtained. This review focuses on two key issues regarding oxLDL in vivo; its involvement in the initiation of atheromatous lesion development, and the characterization of its modified structures in vivo.

Chronic diabetic complications are mostly caused by vascular disorders, with only a few effective treatments or preventive measures currently available. In this study, we investigated the effects of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D), a fungus-derived compound that inhibits both the epoxide hydrolase and phosphatase activities of soluble epoxide hydrolase (sEH), using human umbilical vein endothelial cells (HUVECs) in a high glucose treatment model. When HUVECs were treated with high glucose (30 mM) for 24 h, cell viability decreased to 69% compared with that under normal glucose (5.6 mM) conditions. When SMTP-44D was added, cell viability increased to 111%. In addition, nitric oxide levels in HUVECs decreased to 52% after 24 h of high-glucose treatment but increased to 82% after SMTP-44D treatment. Under the same conditions, high-glucose treatment increased intracellular reactive oxygen species levels and reduced Akt activation. SMTP-44D significantly improved both these changes, compared with the high glucose group. Under high glucose conditions, it is likely that oxidative stress and the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway are involved in endothelial dysfunction, and that SMTP-44D restores vascular function by acting on these pathways. In this study, we demonstrated, for the first time, SMTP-44D improves diabetic vascular endothelial dysfunction, suggesting that it may be a novel therapeutic and preventive candidate for the treatment of chronic complications of diabetes.

Neuregulin 1 (NRG1), a member of the epidermal growth factor (EGF) family, regulates the development, differentiation, proliferation, and plasticity in multiple tissues through its binding to ErbB3 and ErbB4 receptors. In the cardiovascular system, NRG1 plays a crucial role in cardiac development, physiological function, and cell survival. Since NRG1 exerts cardioprotective effects through its interaction with ErbB2/ErbB4 and ErbB4 homodimers on cardiomyocytes, the administration of recombinant human NRG1 has the potential for the treatment of heart failure. ErbB2 is known as human epidermal growth factor receptor 2 (HER2), which is overexpressed in approximately 20% of breast cancers. Trastuzumab (TRZ), a humanized monoclonal antibody targeting ErbB2/HER2, is used for the therapy of HER2-positive breast cancer. However, cardiotoxicity has been observed in approximately 5-10% of patients treated with TRZ. Risk factors for the onset of cardiotoxicity include the use of anthracyclines, hypertension, and diabetes. However, the mechanism linking diabetes and TRZ-induced cardiotoxicity remains unclear. Recently, we reported that the serum levels of NRG1 were elevated in the mouse model of diabetic cardiomyopathy. We found that the up-regulated NRG1 compensates for insulin deficiency to maintain systolic function in the early stage of diabetic cardiomyopathy. This review aims to discuss the physiological roles of NRG1-ErbB2 signaling in the cardiovascular system, the cardioprotective effects of NRG1 and its clinical applications, and the molecular mechanisms of TRZ-induced cardiotoxicity through the blockade of the NRG1-ErbB2 signaling pathway.

Rat kidney tissue slices are expected to be useful for an in vitro evaluation of drug-induced kidney injury (DIKI). We previously established a primary culture of rat kidney tissue slices using gas-permeable plates. However, polydimethylsiloxane (PDMS) exhibits a significant adsorption of lipophilic drugs, leading to limitations in DIKI evaluation. The aim of the present study was to evaluate a gas-permeable InnoCell™ non-treated plate made of polyolefin with low adsorption of lipophilic compounds for the primary culture of rat kidney tissue slices as an in vitro DIKI evaluation system. Drug concentrations in the medium were measured 24 h after the addition of 9 drugs to PDMS plates and InnoCell™ non-treated plates. Intra-tissue ATP levels and histopathology of rat kidney tissue slices were examined on Day 3 of culture. As a result, the InnoCell™ non-treated plates exhibited lower adsorption rates for sunitinib, cyclosporine A, and alectinib than the PDMS plates. Intra-tissue ATP levels were maintained, and immunohistochemical staining of megalin and aquaporin 1 was observed for up to 3 d. Furthermore, exposure to nephrotoxic lipophilic drugs reduced the ATP content in slices compared to that in non-treated slices. These results suggest that the primary culture of rat kidney tissue slices using InnoCell™ non-treated plates is useful for the DIKI evaluation of lipophilic drugs compared with conventional PDMS plates.

Patients with chronic kidney disease (CKD) who develop sepsis experience worse prognoses; however, the impact of CKD on the incidence of sepsis has not been systematically investigated. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of Medical Literature Analysis and Retrieval System Online, Web of Science, the Cochrane Register of Controlled Trials, and ClinicalTrials.gov was performed for literature published prior to May 22, 2025, comparing the onset of sepsis in patients with or without CKD. The risk of bias was determined using the Risk of Bias in Nonrandomized Studies of Interventions tool. This study was registered with the International Prospective Register of Systematic Reviews (CRD42023465075). A total of 14 studies met the inclusion criteria for the systematic review. Of these, 5 examined community-acquired sepsis, 2 focused on intensive care unit-acquired sepsis, and the rest investigated surgery-acquired sepsis. Most studies enrolled populations aged over 65 years; 2 assessed age-related sepsis risk. One study evaluated sepsis occurrence in patients with end-stage CKD, while 3 studies stratified this association by estimated glomerular filtration rate (eGFR). Nearly all studies demonstrated an increased risk of sepsis among patients with CKD, with the risk progressively increasing as eGFR declined. Additionally, 2 studies reported that CKD elevated the risk of sepsis regardless of age, and all included studies indicated a low risk of bias. We indicate that patients with CKD may have a higher risk of developing sepsis than individuals without CKD.

We summarized the recent findings on the acute myocardial effects of several flavonoids, whose long-term beneficial effects through antioxidant activity has attracted attention. Polymethoxyflavones, such as sudachitin, demethoxysudachitin, and nobiletin, showed chronotropic and inotropic effects; the effects were milder than those of β-adrenoceptor agonists. Their strength of action appeared to be related to the number of methoxy groups in the chemical structure. Sudachitin also showed strong vasorelaxant effect causing full relaxation. Quercetin showed positive lusitropic effects in both normal and diabetic myocardium; this was probably mediated by enhancement of Ca²⁺ sequestration into the sarcoplasmic reticulum by the Ca²⁺ ATPase. Hesperetin inhibited the spontaneous firing of action potential in the pulmonary vein myocardium; the chronotropic inotropic and lusitropic effects were weak or not observed. Thus, each flavonoid compound has characteristic pharmacological effects probably through their action on specific cellular targets. Further investigation of their effects would provide insights for the development of therapeutic agents for heart diseases such as heart failure and arrhythmia.

We have established a proarrhythmic rabbit model of acute atrioventricular block (AVB) with severe bradycardia to detect delayed rectifier K⁺ channel current (I_Kr) blocker-induced torsade de pointes (TdP). To better understand the role of β-adrenoceptors in this model, we investigated the effect of the β-adrenoceptor blocker metoprolol against an I_Kr blocker dofetilide-induced TdP. AVB was induced by catheter ablation under isoflurane anesthesia, and the ventricles were electrically paced at a constant rate of 60 beats/min throughout the experiments. Monophasic action potentials (MAPs) were recorded from the right ventricle. In the non-treated control rabbits (n = 5), intravenous administration of an I_Kr blocker dofetilide (25 µg/kg) prolonged the MAP duration (MAP₉₀) by 90 ± 38 ms, which led to the induction of TdP in four of the five animals. In rabbits receiving the β-adrenoceptor blocker metoprolol (10 µg/kg/min, n = 5), the same dose of dofetilide prolonged MAP₉₀ by 205 ± 31 ms, whereas TdP did not occur in this group. Meanwhile, the incidence of dofetilide-induced R-on-T-type premature ventricular contractions, representing an arrhythmogenic trigger, was lower in metoprolol-treated rabbits than in non-treated control rabbits. These results indicate that metoprolol exerted an overall antiarrhythmic effect by strongly suppressing TdP generation induced by dofetilide, despite its proarrhythmic action of enhancing repolarization prolongation. This highlights the critical role of β-adrenoceptors in facilitating arrhythmogenic triggers under conditions of excessive repolarization delay.

Three-dimensional (3D) hepatocyte spheroid cultures offer an advanced in vitro model for investigating liver function and drug metabolism; however, oxygen diffusion limitations restrict spheroid size and functionality. In the present study, we developed a 3D spheroid culture system using HepaRG, a human hepatoma-derived cell line that retains drug-metabolizing enzymes, and oxygen-permeable plates composed of 4-polymethyl-1-pentene (PMP) to improve oxygen availability and metabolic performance. Morphological analysis showed enhanced spheroid circularity and compactness in the PMP culture, implying enhanced cell-cell adhesion. Hypoxic imaging revealed that PMP plate-based cultures markedly reduced central hypoxia, enabling the formation of spheroids with up to 20000 cells. Using clozapine, a low-clearance antipsychotic drug with limited metabolic elimination that is metabolized by monooxygenases, including CYP3A4 and flavin-containing monooxygenase (FMO), we observed an enhanced decline in clozapine levels in PMP plates compared with the clozapine levels seen in the conventional polystyrene plates. Furthermore, the mRNA and protein-expression levels of CYP3A4 and FMO3 were upregulated in the spheroids cultured on PMP plates. These results suggest that improved oxygenation enhances hepatic functionality in 3D cultures by maintaining cell viability and promoting the expression of drug-metabolizing enzymes. Therefore, the PMP plate-based spheroid model offers a practical and physiologically relevant platform for investigating drug metabolism and hepatotoxicity.

Photoacoustic imaging (PAI) is a hybrid imaging modality that captures ultrasound signals produced by thermoelastic expansion when pulsed laser light is absorbed by optical absorbers, enabling visualization of biological tissues at greater depths than those of conventional fluorescence imaging. While PAI has been conventionally used for biological, structural, and morphological studies, showing promise for imaging calcium dynamics in cardiac tissue, its practical implementation remains undemonstrated. In this study, we implemented a sectional excitation strategy using a thin, sheet-shaped laser beam to confine optical excitation to defined tissue planes. We applied this approach to photoacoustic imaging of a perfused bullfrog heart loaded with liposome-encapsulated calcium-sensitive dye. We successfully achieved real-time visualization of calcium dynamics within the atrial cross-section, while simultaneous electrocardiographic recordings enabled temporal correlation between photoacoustic signal fluctuations and cardiac electrical activity. This method provides a less-invasive approach to assess calcium transients in deep tissue, and broadens the application of PAI from morphology to physiological function. These findings highlight the potential of this optical-acoustic hybrid modality as a powerful tool for calcium imaging in physiological and pharmacological studies involving deep-tissue organs-particularly in applications such as heart imaging, where conventional optical techniques are limited by shallow penetration depth.

Parkinson's disease (PD) is a progressive neurological disorder with an unclear etiology. Nonetheless, abnormal cholesterol metabolism is considered an environmental risk factor. MitoNEET (mNT) is an iron-sulfur cluster protein located in the outer mitochondrial membrane. mNT dysfunction is involved in the pathology of several diseases, including PD. However, the cause of mNT dysfunction remains unclear. Therefore, we hypothesized that increased intracellular cholesterol levels may reduce mNT function and increase reactive oxygen species (ROS) levels, resulting in neuronal cell death and PD progression. In this study, we investigated the effects of cholesterol on cell viability and mNT levels in human neuroblastoma (SH-SY5Y) cells. Cholesterol reduced cell viability and mNT protein levels and increased ROS generation. Pioglitazone, an mNT activator, decreased cholesterol-induced ROS generation but did not rescue cell viability, suggesting that reduced mNT levels may be involved but are not the sole cause of cholesterol-induced cell death. Additionally, the viability of cells treated with rotenone, 6-hydroxydopamine, and 1-methyl-4-phenylpyridinium in the presence of cholesterol was measured. However, no significant enhancement in cell death was observed. Moreover, the toxic compounds did not reduce mNT levels, indicating that mNT is not involved in toxic compound-induced cell death. In summary, these results indicate that cholesterol induces cell death, reduces mNT protein levels without suppressing transcription, and increases ROS generation, which may affect PD development. Further assessment of the mechanisms associated with abnormal intracellular cholesterol metabolism, reduced mNT levels, and cell death may lead to the discovery of novel treatments for PD.