Shota Yanagida, Hiroyuki Kawagishi, Yasunari Kanda
{"title":"[Global trends in drug development using alternatives to animal testing].","authors":"Shota Yanagida, Hiroyuki Kawagishi, Yasunari Kanda","doi":"10.1254/fpj.26042","DOIUrl":"10.1254/fpj.26042","url":null,"abstract":"<p><p>In recent years, declining success rates and rising development costs have posed major challenges in drug development, highlighting the need for more efficient and rational approaches to evaluating drug efficacy and safety. Although non-clinical studies have traditionally relied primarily on animal experiments, adverse events that are difficult to predict continue to emerge during clinical trials and post-marketing, underscoring limitations in human extrapolation. In this context, new approach methodologies (NAMs), including human cell-based models and in silico analyses, have gained increasing international attention for improving predictivity while contributing to the 3Rs principles. This review outlines international and domestic regulatory trends in NAMs and highlights recent advances in organ-specific toxicity assessment using human-relevant models. For cardiotoxicity, contractility assays using human iPSC-derived cardiomyocytes have demonstrated the ability to predict chronic contractile dysfunction and are expected to support anticancer drug safety assessment. In neurotoxicity, platforms combining rat cortical neurons and human iPSC-derived neurons with multi-electrode array system have improved sensitivity for detecting seizure risk. In hepatotoxicity, three-dimensional culture systems and hepatocytes derived from humanized liver chimeric mice have shown promise for predicting drug-induced liver injury. Future efforts should focus on defining context of use and establishing reproducibility and reliability to enable broader regulatory acceptance of NAMs. As regulatory frameworks continue to evolve worldwide, guidelines are expected to be developed or updated based on a weight-of-evidence approach integrating in vitro and in silico data.</p>","PeriodicalId":12208,"journal":{"name":"Folia Pharmacologica Japonica","volume":"161 5","pages":"347-355"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"[Light stress-induced damage to intracellular membrane organelles and its preventive strategies].","authors":"Wataru Otsu","doi":"10.1254/fpj.26030","DOIUrl":"https://doi.org/10.1254/fpj.26030","url":null,"abstract":"<p><p>Photoreceptor cells in the retina are highly specialized sensory cells that function as light receptors. During the conversion of light into neural signals, photoreceptors are constantly exposed to oxidative stress. Although environmental stressors, such as excessive light exposure, have been implicated in the progression of various retinal diseases, including dry age-related macular degeneration (AMD), the molecular mechanisms underlying the light-induced stress response remain incompletely elucidated. Excessive light exposure triggers the endoplasmic reticulum (ER) stress response in cells and also induces mitochondrial dysfunction characterized by depolarization and fragmentation, ultimately leading to cell death. We have shown that compounds derived from natural products, such as delphinidins and pentadecyl, exert protective effects against blue light-induced cellular damage. Furthermore, crocetin, a natural carotenoid pigment, has been shown to suppress ultraviolet-A (UV-A)-induced mitochondrial fragmentation in corneal epithelial cells. In this review, we provide an overview of light stress-induced injuries to intracellular membrane organelles, particularly mitochondria and the ER, and the cellular response mechanisms that are mediated through these organelles. These findings suggest that maintaining the homeostasis of intracellular membrane organelles represents an important therapeutic target for the prevention and treatment of retinal degenerative diseases.</p>","PeriodicalId":12208,"journal":{"name":"Folia Pharmacologica Japonica","volume":"161 4","pages":"257-262"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tomoka Morita, Moe Hirosawa, Takeshi Itabashi, Tatsuo Miyamoto
{"title":"[Cholesterol in the ciliary membrane as a therapeutic target of polycystic kidney].","authors":"Tomoka Morita, Moe Hirosawa, Takeshi Itabashi, Tatsuo Miyamoto","doi":"10.1254/fpj.25078","DOIUrl":"10.1254/fpj.25078","url":null,"abstract":"<p><p>Primary cilia are non-motile, microtubule-based cellular protrusions that sense extracellular chemical and mechanical cues, converting them into intracellular signals. Ciliary dysfunction causes ciliopathies including polycystic kidney disease and retinal degeneration. The ciliary membrane is highly enriched in cholesterol, which is essential for the physiological function of ciliary-localized receptors, including G-protein-coupled receptors (GPCRs) and ion channels. Defective de novo cholesterol synthesis, as seen in Smith-Lemli-Opitz syndrome (SLOS), causes typical ciliopathy-like symptoms, suggesting cholesterol deficiency is a core mechanism. We previously identified a pathway where a subset of peroxisomes moves via microtubules to the ciliary base and supplies cholesterol to the ciliary membrane. Furthermore, we found that the mechanosensory cation channel polycystin (PKD1/PKD2) complex, the product of genes underlying Autosomal Dominant Polycystic Kidney Disease (ADPKD), exhibits cholesterol-dependent ciliary localization. Focusing on the ADPKD-associated missense variant p.L517R in the cholesterol-binding site of polycystin-2 (PKD2), we generated mutant mice that displayed ciliopathy spectrums, including situs inversus and polycystic kidneys. The L517R mutant protein showed impaired ciliary localization despite normal channel activity. Intriguingly, exogenous cholesterol administration rescued the ciliary trafficking defect of PKD2 and the expanded epithelial lumen structure in the Zellweger syndrome-modeled cells (peroxisome biogenesis disorder) but not in the PKD2 L517R mutant cells. These findings indicate that the ability of PKD2 to directly bind ciliary membrane cholesterol is essential to prevent ADPKD. This review highlights ciliary cholesterol as a potential therapeutic target for ADPKD.</p>","PeriodicalId":12208,"journal":{"name":"Folia Pharmacologica Japonica","volume":"161 3","pages":"171-176"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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